ULASAN

HIPOKSIA DAN METABOLISME Hipoksia

sinyal melalui mTOR dan respon protein
dilipat pada kanker
Bradly G. Wouters * || dan Marianne Koritzinsky *
Abstrak | Hipoksia terjadi di sebagian besar tumor, mempromosikan angiogenesis, metastasis
dan resistensi terhadap terapi. Tanggapan hipoksia yang diatur di bagian melalui aktivasi dari
keluarga faktor hipoksia diinduksi faktor transkripsi (HIFs). Baru-baru ini, dua tambahan O
mamalia 2
-sensitive Target sinyal dari jalur rapamycin (mTOR) juga kinase telah dan terlibat: sinyal sinyal
melalui melalui
aktivasi respon protein dilipat
(UPR). Meskipun mereka diaktifkan secara independen, bukti yang berkembang menunjukkan
bahwa HIF-, mTOR- dan UPR tergantung respon terhadap hipoksia tindakan secara terpadu,
saling mempengaruhi jalur hilir lainnya dan umum yang mempengaruhi ekspresi gen,
metabolisme, kelangsungan hidup sel, tumorigenesis dan pertumbuhan tumor.
Rapamycin
The mikro tumor manusia tidak seperti yang
mempengaruhi beberapa komponen
dari kedua jalur tersebut, An macrolide antijamur
dari setiap jaringan normal, ditandai dengan hetero- ekstrim
yang masing-masing adalah unik
tergantung pada sever- diproduksi oleh bakteri, yang biasa digunakan untuk mencegah posting -transplantation
penolakan organ karenadi
geneities pasokan gizi, pH dan oksigenasi.dan
Ity / atau durasi hipoksia. Akibatnya, fitur unik cel- berkembang
sebagai konsekuensi dari perubahan
lular respon terhadap hipoksia di dalam dan di antara yang
berbeda dalam metabolisme dan status proliferasi tumor
tumordapat menunjukkan heterogenitas yang signifikan.
tindakan imunosupresif.
sel bersama-sama dengan pasokan vaskular yang sangat tidak teratur.
Meskipun demikian, munculnya mTOR
dan UPR Rapamycin mengikat FKBP12,
Selain perubahan genetik dan epigenetik yang
jalur sebagai kontributor penting untuk
toleransi hipoksia yang pada gilirannya mengikat dan menghambat mTORC1.
terjadi pada kanker, mikro ini sekarang recog-
dan fenotip yang merugikan tumor hipoksia sarankan nized
menjadi kontributor penting untuk diubah gen
peluang baru untuk terapi kanker yang
ditargetkan. * Ontario Cancer Institute,
ekspresi dan fungsi sel
(Gambar.
1).Secara khusus,
The Ulasan saat ini berfokus pada
perkembangan terakhir Princess Margaret Hospital, University Health Network, Toronto, Ontario, Kanada.
Departemen Radiasi Onkologi, Universitas
laboratorium dan bukti klinis sangat diasosiasikan-
yang telah diklarifikasi pemahaman kita tentang bagaimana
perubahan makan kekurangan dalam oksigenasi (hipoksia) dengan perkembangan tumor, pertumbuhan, metastasis
dan respon yang buruk terhadap
O
2
therapy1. Hipoksia mengubah perilaku sel tumor Toronto, Toronto, Ontario, Kanada.
ketersediaan pengaruh sinyal melalui mTOR dan jalur UPR serta kepentingan relatif dari jalur ini di
fenotipehipoksia.
Kami juga tinggi-melalui
sejumlah O
2
Department dari Medis Biofisika, Universitas
daerah cahaya di mana penelitian tambahan diperlukan untuk clar- ify pemahaman kita tentang jalur ini dalam
kaitannya dengan hipoksia tumor.
Toronto, Toronto, Ontario, Kanada.
Hipoksia dan mTOR || Selektif
Therapeutics Program, Ontario Institute for Cancer Research, Toronto, Ontario, Kanada.
jalur -sensitive, yang terbaik dipahami dari yang yang dimediasi oleh keluarga hypoxia- diinduksi faktor faktor
transkripsi (HIFs). Peraturan Baru-baru ini, dua jalur lain yang independen mempengaruhi ekspresi gen dan proses
penting untuk tumor pertama sel perilaku ini terjadi melalui telah terbukti menjadi O dari 2
sebuah -sensitive. impor-
Hipoksia mempengaruhi mTOR sinyal di beberapa titik. The mengintegrasikan mTOR kinase dan mengirimkan sinyal
dari tant integrator sinyal metabolik, kinase yang mamma-
beragam jalur sinyal untuk mengatur sel
Maastricht Radiasi
Target lian dari rapamycin (mTOR, juga dikenal sebagai FRAP1),
kelangsungan hidup dan pertumbuhan
melalui perubahan mRNA translasi Onkologi, GROW-sekolah untuk
dan efektor hilir yang mengatur para
inisiasi,biogenesis ribosom, autophagy
dan metabolisme Onkologi dan perkembangan Biologi, Universitas Maastricht, Maastricht, Belanda.
tion sintesis protein, autophagy dan apoptosis sensi-
(Ulasan di
REF. 2 tivity. Yang kedua adalah melalui aktivasi respon protein dilipat (UPR), program transkripsi Correspondence
untuk BGW
dan perubahan translasi yang terjadi sebagai e-mail konsekuensi :
bwouters@uhnresearch.ca doi: 10.1038 / nrc2501 Diterbitkan
online).Sebagai bagian dari mTOR kompleks 1 (mTORC1), aktivasi mTOR dalam kondisi nutrient- dan energi penuh
merangsang sintesis protein dan pertumbuhan sel melalui fosforilasi protein ribosom S6 kinase dari retikulum
endoplasma (ER) stres. Kontrol UPR
(p70S6K, juga dikenal sebagai RPS6KB1), inisiasi eukariotik
beberapa proses hilir, termasuk proteinpro
faktor4E protein yang mengikat 1 (4E-BP1) dan duction
eukariotik,
pematangan protein
dan degradasi, sel METABO-
faktor elongasi 2 kinase (EEF2K ) 3. Mengingat peran ini,
10 Oktober 2008
lism dan kematian sel. Hipoksia telah ditunjukkan untuk
ini mungkin tidak mengejutkan bahwa aktivitas mTORC1 juga
NATURE ULASAN | KANKER VOLUME 8 | November 2008 | 851
ULASAN
Sekilas
Salah satu fungsi utama dari kompleks mTORC1 adalah untuk mengatur langkah inisiasi translasi mRNA.
tanggapan Seluler hipoksia dimediasi oleh kedua faktor (HIF) -tergantung kekurangan sinyal hipoksia-diinduksi.
jalur dan pameran HIF-independen jalur sensitivitas yang unik. dengan masing-masing beratnya ini dan O
2 durasi -sensitive
dari O
2
Hipoksia menghambat sinyal hilir kinase sasaran mamalia dari rapamycin (mTOR) dan terjemahan inisiasi mRNA
melalui beberapa mekanisme independen. Signalling melalui jalur ini muncul untuk mempengaruhi baik
perkembangan tumor dan toleransi hipoksia pada tumor canggih.
paparan hipoksia berat menyebabkan retikulum endoplasma (ER) stres dan menyebabkan aktivasi cepat dari
respon protein dilipat (UPR). UPR mengatur beberapa jalur efektor hilir yang bersama-sama berfungsi untuk
mempromosikan toleransi hipoksia.
hipoksia sinyal melalui mTOR dan hasil UPR perubahan signifikan dalam terjemahan mRNA yang mempengaruhi
ekspresi gen dan perilaku selular di sel hipoksia. Menargetkan jalur ini dapat mengurangi atau pertumbuhan tumor
yang lambat.
Banyak konsekuensi seluler hipoksia secara bersama-sama dipengaruhi oleh tumpang tindih O tumor 2
metabolisme -sensitive, jalur. autophagy HIF, mTOR dan dan ER UPR homeostasis.
signaling selama pengaruh hipoksia
Banyak saat ini dan eksperimental agen antikanker menyebabkan stres ER dan mengaktifkan UPR, dan dengan
demikian dapat menunjukkan toksisitas selektif untuk sel hipoksia. Sebaliknya, hipoksia
penghambatan hipoksia hasil mTORC1 berkurang fosforilasi dari 4E-BP1 dan hubungannya meningkat dengan
protein cap mengikat terjemahan eukariotik inisiasi tiation faktor 4E (EIF4E) 12. Hal ini untuk mencegah inisiasi
translasi cap tergantung dengan mencegah asosiasi EIF4E dengan EIF4G. Menariknya, hipoksia juga bisa negatif
mengatur EIF4E independen dari mTOR dan 4E-BP1 dengan mempromosikan kerjasama dengan EIF4E transporter
(4E-T) 13, sebuah protein yang bertanggung jawab untuk transportasi ke dalam nukleus dan sitoplasma p-bodies14
yang menyimpan dan keheningan mRNA13, 15. Akibatnya, hipoksia mengarah untuk mendukung pression
terjemahan cap-dependent melalui beberapa jalur mTOR tergantung dan mTOR-independen. Pentingnya biologis
peraturan ini, terlepas dari apa yang sudah diketahui untuk mTOR, baru mulai akan dijelaskan, dan data mendukung
peran penting baik dur- ing tumorigenesis dan dalam keganasan tumor canggih.
sinyal melalui jalur mTOR kemungkinan untuk mempengaruhi kemanjuran dari banyak obat baru yang menargetkan
jalur ini.
tanggapan mTOR hipoksia penting dalam genesis tumori-. Ada dua cara berbeda yang hipoksia tion regulasi dari
mTORC1 signaling mungkin penting dalam kanker. mTORC1 sensitif untuk melalui O
2
kekurangan. Bahkan, hipoksia menghambat beberapa jalur, khususnya di con-
Yang pertama adalah sehubungan dengan fakta bahwa banyak dari regulator negatif dikenal mTORC1 signaling
memiliki Autophagy Secara harfiah, "diri makan", autophagy adalah proses dimana komponen seluler
cert dengan tekanan atauketika kondisi hipoksia yang
telah terbukti berfungsi sebagai bona fide tumor suppres- tahan
lama (kronis)
(2 Gambar.)
 sors atau setidaknya untuk menekan pertumbuhan tumor. Ini termasuk TSC1 dan TSC2, yang bermutasi di sclero-
tuberous ditangkap, terdegradasi dan
sis syndrome (yang ditandai dengan
hamartomas), daur ulang menggunakan mesin lisosom. Ini adalah satu-satunya proses selular yang dapat
menurunkan kompleks protein kovalen dan organel.
LKB1 (juga dikenal sebagai protein serin / treonin kinase 11 (STK11)), yang bermutasi di Peutz-Jeghers syndrome
(ditandai dengan pertumbuhan beberapa neoplasma), dan PTEN, regulator negatif phosphoinositide 3-kinase (PI3K)
sinyal yang hilang di sejumlah protein pematangan pematangan besar protein disekresikan atau membran-
ditakdirkan biasanya melibatkan N-linked
dari cancers2. Dengan demikian, adalah mungkin bahwa hipoksia, seperti regulator negatif lain dari mTORC1
signaling, dapat berfungsi untuk menekan pertumbuhan tumor dan pembangunan. glikosilasi selama
Hipoksia diduga berasal di awal
tumorigenesis sebagai sel co-translasi impor ke UGD, serta modifikasi glycan, oksidatif
lipat.Dua jalur tersebut dimediasi melalui aktivasi hipoksia dari tuber- ous protein sclerosis
1 (TSC1) -TSC2 kompleks. Arsham dan rekan pertama menunjukkan bahwa eksposur singkat hipoksia sederhana
insulin-mediated (1% O
2
untuk stimulasi kurang dari 1 jam dari mTORC1 cukup) dan mencegah fosforilasi dari target p70S6K dan 4E-BP1
berikut starvation4 serum. Dengan kondisi tersebut, penghambatan mTOR terjadi melalui jalur HIF1-independen
yang melibatkan AMP-activated protein kinase (AMPK) - aktivasi tergantung dari TSC1-TSC2
(REF
5.).Beberapa kelompok telah menunjukkan bahwa hipoksia juga dapat
mengaktifkan TSC1- TSC2 melalui regulasi transkripsi dari REDD1 (juga
berkembang biak dan suplai darah mereka. Batas
dan isomerisasi karena disulfida pembentukan ikatan
dikenal sebagai DDIT4) 6-8. Induksi REDD1 tampaknya cukup untuk mengaktifkan kembali TSC1-TSC2 dengan
melepaskan TSC2
O lapisan. 2
Tingkat difusi dalam hipoksia jaringan adalah 100-200 yang telah m atau ditampilkan sekitar 10-20 untuk
menghambat sel
dalam lumen ER.
dari pertumbuhan ciation faktor-diinduksi dengan 14-3-3
(REF. 9)
atau energi yang disebabkanasso-
tances mTORC1jauh sinyal yang lebih kecil (misalnya, dari this4. 1% O
Akibatnya,
2)
timbul padadis
pendampingmenemani protein untuk membantu lipat dan mencegah agregasi. Kontrol kualitas yang ketat
diterapkan.Dengan cara ini, hipoksia mungkin memusuhi jalur pertumbuhan
mempromosikan lain yang sig-
meningkat bahkan kecil dalam proliferasi disebabkan oleh awal
nal untuk TSC1-TSC2 melalui Akt. Hipoksia juganega-
aktivasi onkogenikdapat menyebabkan hipoksia. Berkembang biak
sebelum rilis protein dari
mTORC1-masing mengatur melalui protein yang mengganggu interaksi antara mTOR dan RHEB. pro
Sel-seljuga menunjukkan kenaikan tingkat O
2
mesin lipat dan ekspor ke Golgi.
myelocytic tumor leukemia penekan (PML) telah dilaporkan untuk mengikat mTOR selama hipoksia dan
menonaktifkan itu
fenotipe hipoksia Ditandai dengan adaptif
melalui penyerapan di bodies10 nuklir. Demikian pula, hipoksia diinduksi protein proapoptotic BNIP3 (Bcl2 /
tanggapan seperti penurunan
adenovirus E1B 19 kDa protein-berinteraksi protein 3) proliferasi dan sintesis protein,
tingginya tingkat glikolisis dan metabolisme anaerobik, meningkat
dilaporkan untuk mengatur mTOR dengan mengikat langsung ke RHEB11 . Relevansi fisiologis mTOR tion regulasi
oleh PML dan BNIP3 masih perlu ditentukan. sekresi faktor angiogenik
Namun, masing-masing tampaknya setidaknya sebagian bertanggung jawab untuk dan
potensi metastasis meningkat. Ini, bersama-sama dengan kerentanan terhadap jalur kematian, akhirnya menentukan
toleransi hipoksia.
tion konsumsi yang mungkin memperburuk depletion16 ini. Jika hipoksia memang bertindak sebagai penghalang
untuk pertumbuhan tumor pada tahap awal yang diharapkan bahwa sel-sel tumor akan deregulasi sinyal ini selama
karsinogenesis. Dengan cara ini, hipoksia bisa mendorong pemilihan mutasi yang memberikan keuntungan
pertumbuhan melalui dereg modulasi dari mTORC1 di cara yang analog dengan seleksi mutasi di jalur yang
memberikan resistensi terhadap death17 sel. Ide ini didukung oleh data yang menunjukkan bahwa hilangnya PML
mengarah ke peningkatan neoangiogenesis dan inhibisi hipoksia diinduksi mTOR, sebagai PML-KO
bahwa ini dapat membantu tumorigenesis10. sel atau kecil
campur knockdown RNA-dimediasi
Meskipun ide ini belum secara resmi diuji BNIP3 mengurangi
defosforilasi hipoksia diinduksi
dalam model tumor, ada beberapa bukti yang menunjukkan dari
p70S6K10,11.
bahwa hipoksia kurang efektif menghambat mTORC1
852 | November 2008 | VOLUME 8 www.nature.com/reviews/cancer
ULASAN
Sitoplasma
Hipoksia
mTOR
Gambar transkripsi 1 | Selular dan mRNA O
2
-sensing terjemahan. jalur. Pertama, hipoksia Tiga utama menstabilkan O
2 jalur hypoxia-inducible -sensing
mempromosikan faktor 1 hipoksia (HIF1 mTOR kompleks 1 (mTORC1). Salah satu dari dua kompleks protein
(bersama dengan mTORC2) diketahui pelabuhan mTOR. MTORC1 mengandung mTOR, mLST8, PRAS40 dan
raptor. aktivasi Its merangsang sintesis protein dan pertumbuhan sel melalui fosforilasi p70S6K, 4E-BP dan EEF2K.
TSC1-TSC2 kompleks ini kompleks tumor penekan TSC1 dan TSC2, juga dikenal sebagai hamartin dan tuberin,
masing-masing, menampilkan aktivitas protein GTPase-activating terhadap RHEB, sehingga regulasi negatif
mTORC1. aktivitas ini negatif diatur oleh Akt dan Erk-dimediasi fosforilasi TSC2, dan diatur secara positif oleh AMPK-
dependent TSC2 fosforilasi.
Cap-dependent terjemahan modus utama terjemahan inisiasi mRNA yang mengandalkan perekrutan dari subunit
ribosom kecil dan faktor terkait melalui struktur 5 tutup mRNA. Hal ini memerlukan pengikatan kompleks EIF4F di
cap, yang bertindak sebagai perancah untuk kompleks ribosom.
Hamartomas Tumor jinak yang dapat menyebabkan gejala karena lokasi dan ukuran mereka.
SIFAT ULASAN | KANKER VOLUME 8 | November 2008 | 853
toleransi dengan
mengatur),memfasilitasi
heterodimerisasi dengan HIF1 dan aktivasi transkripsi banyak gen. Kedua, hipoksia memicu respon protein dilipat
(UPR) oleh aktivasi retikulum endoplasma (ER) stres sensor PKR-seperti ER kinase (merembes), inositol-
membutuhkan protein 1 (IRE1) dan, kemungkinan besar, mengaktifkan faktor transkripsi 6 (ATF6 ). IRE1 dan ATF6
baik berkontribusi respon transkripsi sedangkan merembes menyebabkan penghambatan terjemahan mRNA. Ketiga,
aktivitas mTORC1, sebuah kompleks yang mengandung target mamalia dari rapamycin (mTOR) kinase, yang
mengintegrasikan dan mengirimkan sinyal pertumbuhan positif dan negatif terhadap mesin translasi, dihambat oleh
hipoksia. Perubahan dalam terjemahan mRNA dapat sangat gen spesifik dan dengan demikian juga dapat secara
signifikan berkontribusi untuk diferensial ekspresi protein selama hipoksia. Bersama tiga jalur ini mempengaruhi
fenotip sel hipoksia dengan mengubah metabolisme, angiogenesis, autophagy dan ER homeostasis. XBP1, X-box-
binding protein 1.
pada sel tumor daripada di jaringan normal. Misalnya, sedangkan hipoksia sintesis protein secara efektif
menghambat melalui penurunan fosforilasi 4E-BP1 di sel epitel payudara simultan diabadikan spon-, efek ini secara
signifikan kurang jelas di lini sel yang berasal dari lebih kanker payudara stadium lanjut yang menunjukkan consti-
tutive mTORC1 activity18. Demikian pula, hilangnya fungsi TSC2 atau PTEN, yang menyebabkan aktivasi konstitutif
aktivitas mTORC1, dapat mencegah hipoksia dari inhibit- ing mTOR19. Bersama-sama, data ini mendukung dengan
kemungkinan bahwa mutasi pada jalur mengatur mTORC1 dapat terjadi di bagian untuk memotong hipoksia-
dimediasi mTOR penghambatan. Ini akan menjadi penting untuk menguji gagasan ini dalam model yang lebih ketat
dari perkembangan tumor.
Hipoksia dan mTOR sinyal pada tumor canggih. Sebaliknya, data yang juga mendukung peran penting untuk regulasi
hipoksia dari mTORC1 dalam konteks canggih, tumor ganas. Meskipun mTOR deregulasi selama proses
karsinogenesis, ada semakin banyak bukti yang menunjukkan bahwa sel-sel tumor terkena stres hipoksia berat perlu
untuk mempertahankan atau membangun kembali regulasi atas jalur sinyal ini sebagai sarana untuk mengontrol
sintesis protein, metabolisme energi dan kelangsungan hidup sel ( disebut sebagai toleransi hipoksia). Pada
pandangan pertama, ini tampaknya bertentangan peran yang disorot di atas di mana mTORC1 memediasi hipoksia
diinduksi
blokdalam pertumbuhan sel dan proliferasi. Salah satu alasan untuk perbedaan ini jelas mungkin berhubungan
dengan Osewa
data2
ketergantungan konsisten dengan mTORC1 peraturan Model. di mana sedang skr
Sintesishipoksia(~ 1% dan proliferasi O
2)
menghambat dalam sel mTORC1 relatif aktivitas, protein origin5,6,18 jinak, sedangkan kebanyakan
jika tidak semua sel menghambat mRNA terjemahan dan proliferasi dalam menanggapi hipoksia lebih
parah (0.1% exposure5. dalamO terakhir
situasiini,2)
20, atau setelah penghambatan lebih lama dari terjemahan mRNA mungkin menjadi penting untuk pelestarian
homeostasis energi yang diberikan ekstrim biaya ATP menghasilkan protein ditambah dengan generasi yang tidak
efisien dari ATP selama hipoksia berat menekankan. Hal ini belum jelas apa penghambatan terjemahan derajat di
bawah kondisi hipoksia lebih parah adalah yang berkaitan langsung dengan tion regulasi dari mTORC1 sendiri.
Knockdown 4E-BP1 tidak lumayan mengubah penghambatan terjemahan yang terjadi pada sel-sel kanker selama
anoksia, menunjukkan bahwa ulators reg- lain kegiatan EIF4E seperti 4E-T dapat berkontribusi untuk effect21 ini.
Meskipun demikian, sel direkayasa untuk kekurangan 4E-BP1 menunjukkan peningkatan sensitivitas terhadap
kematian sel hipoksia diinduksi dan mengembangkan tumor yang telah mengurangi tingkat ATP dan tingkat yang
lebih tinggi dari kematian sel (MG Magagnin et al., Pengamatan tidak diterbitkan), dukungan-ing fungsi penting
protein ini dalam mediasi toleransi hipoksia.
Lumen ER
Degradasi
ATF6
XBP1
Nucleus
ER stres:UPR
HIF1
AAAA
HIF1
Transkripsi
HIF1
global mRNAtranslation
mekanisme toleransiHipoksia
Selektif terjemahan mRNA
ER homeostasis Autophagy metabolisme Angiogenesis
Hipoksia
ATF6
merembes IRE1
Hipoksia
ATF4
ULASAN
Receptor sinyal
subset kecil gen tetap istimewa dijabarkan karena berbagai elemen di 5mereka tidak diterjemahkan
P
wilayah(UTRs; cap-independent) 12
(BOX
1).Dalam ini secara khusus, sejumlah gen, termasuk hipoksia diinduksi PDK1
PI3K Sitoplasma
PAKT
genencoding HIF1 dan faktor pertumbuhan endotel vaskular A (VEGFA), mengandung unsur-unsur peraturan yang
Hipoksia
mendukung terjemahan preferensial dalam kondisi 4E-BP1 hypophosphorylation22. Braunstein dan col 14-3-3
P TSC2 PP
P
TSC2
TSC1 P
REDD1
AMPK
LKB1
liga baru-baru ini menunjukkan bahwa 4E-BP1 dan EIF4GI yang diekspresikan dalam kanker payudara stadium
lanjut dan
ATP
ini memfasilitasi vaskularisasi dan pertumbuhan tumor dengan mempromosikan situs entri ribosom intern terjemahan
-dimediasi dari VEGFA23. Dengan demikian, salah satu alasan untukBNIP3tinggi
RHEB GTP
tingkatRHEB PDB 4E-BP1mungkin untuk memberikan kesempatan untuk menghambat terjemahan cap-dependent
dan untuk mendukung
Hipoksia
ekspresi transkrip cap-independen dalam menanggapi EIF4E EIF4E
ke lingkungan mikro stres. Namun, VEGFA expression
PML
mTOR
sion mungkin bukan satu-satunya keuntungan memiliki tingkat-tingkat tinggi 4E-BP1 di beberapa tumor. Kami
mengusulkan bahwatinggi 4E-T
tingkatdari 4E-BP1 bisa mendapatkan keuntungan pertumbuhan tumor karena EIF4E
memungkinkan untuk meningkatkan kapasitas sintesis protein
P EEF2K
EEF2K P
p70S6K PPP
P
4E-BP1
(lebih dari ekspresi EIF4G atau EIF4E) bawahHipoksia menguntungkan
dikondisi pertumbuhantanpa kehilangan kontrol translasi selama kondisi stres hipoksia. Ini mungkin tertentu- ularly
menguntungkan dalam konteks heterogen
P
EEF2
P S6
EIF4E
Cap
oksigen tumor.
Data menunjukkan bahwa regulasi negatif mTORC1 melalui BNIP3 mungkin memiliki peran yang sama dalam
hipoksia tol- erance dan fenotip ganas. BNIP3 expression EIF4G
sion ditemukan di daerah perinecrotic tumor dari beberapa origins24 dan berkorelasi dengan kelangsungan hidup
miskin dalam kanker paru-sel non-kecil dan endometrium karsinogenik
penerjemahanCap-dependent
mas25,26. Meskipun data ini korelatif, BNIP3elongasi
terjemahan
berlebih telah terbukti secara
langsung meningkatkan Gambar 2 | Penghambatan Target mamalia dari rapamycin (mTOR) signaling oleh
pertumbuhan tumor dalam manner11
rapamycin-sensitif. hipoksia. mTOR, sebagai bagian dari mTOR kompleks 1 (mTORC1), mentransmisikan sinyal
pertumbuhan positif
demikian, BNIP3 dapat meningkatkan
pertumbuhan tumor dalam Serupa dengan mesin translasi melalui kemampuannya untuk memfosforilasi protein
ribosom S6
lar cara untuk itu hipotesis di atas
untuk 4E-BP1: oleh kinase (p70S6K), EEF2K (faktor eukariotik elongasi 2 kinase) dan 4E-BP1 (eukariotik
membatasi aktivitas mTORC1 selama
hipoksia. Mengingat faktor inisiasi translasi 4E (EIF4E) -binding protein 1). Rilis terakhir cap-mengikat EIF4E protein,
yang memungkinkan untuk mengikat protein perancah EIF4G dan memulai penerjemahan topi yang tergantung.
Kegiatan mTORC1 dipengaruhi oleh sejumlah besar positif (hijau) dan negatif (oranye) regulator. Aktivasi bergantung
pada interaksi dengan RHEB GTP-loaded. Data menunjukkan bahwa interaksi ini dapat dihambat selama hipoksia
oleh BNIP3 (Bcl2 / adenovirus E1B 19-kD protein-protein berinteraksi 3) dan / atau promyelocytic leukemia (PML)
supresor tumor. Hipoksia juga menghambat mTORC1 melalui AMP-activated protein kinase (AMPK) dan regulasi
REDD1 tergantung dari kompleks TSC1-TSC2.
Banyakcara yang hipoksia mengatur mTOR, ada kemungkinan bahwa ketergantungan tumor individu pada regulator
tertentu berbeda. Hal ini mungkin menjelaskan peran pro-survival paradoks dari BNIP3 dalam situasi tertentu. Tan
dan rekan menemukan bahwa ekspresi BNIP3 tinggi dikaitkan dengan kelangsungan hidup yang baik pada pasien
kanker payudara dengan karsinoma invasif, padahal ia TSC1-TSC2 menampilkan kompleks GTPase-activating
aktivitas protein terhadap RHEB, sehingga
terkait dengan hasil yang buruk pada
pasien dengan duktal dalam peraturan negatif mTOR. Akhirnya, hipoksia dapat langsung mempengaruhiterjemahan
karsinomadalam situ27. inisiasi mesin
oleh penyerapan EIF4E dan nuklir faktor impor 4E-T untuk inti
 Akhirnya, regulasi mTORC1 dan
terjemahan dan badan pengolahan sitoplasma (P-tubuh). PDK1, piruvat dehidrogenase kinase 1; PI3K,
phosphoinositide 3-kinase.
selama hipoksia juga dapat mempromosikan hipoksia toleran Ance melalui mekanisme kelangsungan hidup sel yang
melibatkan perubahan apoptosis dan / atau autophagy. Hipoksia telah terbukti downregulate Peraturan pro pro-
apoptosis terjemahan selama hipoksia dapat
teins BH3-berinteraksi domain kematian agonis (BID), juga
mendukung pertumbuhan tumor dan / atau kelangsungan hidup dengan cara
Bcl2 antagonis kematian sel (BAD) dan BAX, di bagian terpisah
dari yang homeostasis energi. Baru-baru ini
melalui perubahan dalam terjemahan, mengakibatkan
peningkatan data yang diterbitkan mendukung peran penting untukhipoksia
kelangsungan hidupdan ketahanan terhadap agents28
kemoterapi. regulasi 4E-BP1 pada kanker payudara melaluiabil- yang
mTORC1juga merupakan regulator utama autophagy ity
mempengaruhi penerjemahan gen spesifik. Meskipun 4E-BP1
(Ulasan di
REF.
29)dalam kondisi miskin gizi. fosforilasi
menghambat terjemahan yang paling transponder
Hipoksia dan iskemia dapat menginduksi autophagy, dan skrip
dengan mencegah asosiasi EIF4E dan EIF4G
RNA knockdown gangguan-dimediasi penting di struktur 5 tutup
mRNA (cap-dependent),
protein terkait autophagy seperti sebagai Beclin 1 atau ATG5
854 | November 2008 | VOLUME 8 www.nature.com/reviews/cancer
ULASAN
Box 1 | Peraturan mRNA terjemahan olehhipoksia
kondisihipoksik yang disertai dengan penghambatan
dari60
b
tingkat keseluruhan terjemahan mRNA. Bukti untuk penghambatan ini telah terakumulasi dari
60 40 penggunaan dua tes utama. Tes pelabelan metabolik mencerminkan perubahan dalam sintesis protein dan
telah diamati selama kedua hipoksia berat dan ringan. The
EIF2 4E-BP1-EEF2K 0,9) mn 4
AAAA
yc
0,8
0,7
0,6
60
40
AAAA
0,5
0,4
0,3
poli-ribosom (polysome) assay
T
0,2 (lihat gambar bagian) juga telah
0,1 digunakan untuk memperkirakan
perubahan dalam terjemahan dengan menilai jumlah dan distribusi
5 2 (e
Kontrol cna
40
1 jam anoksia
brosb
60
40
60
40
60
40 Rae iv kisah
neiciffenoitalsnar
0,2% O
 2 0.0% O
2
Gradient kedalaman
0
0 24
48 72 durasi Hipoksia (jam)
polysomesdalam sel . dengan menganalisis distribusi polysome, adalah mungkin untuk menyimpulkan petunjuk
mekanistik mengenai dasar untuk penghambatan synthesis104 protein. The 40S dan 60S subunit ribosom diwakili
oleh 40 dan 60, masing-masing. amplitudo
c
TC
C
C
T
T
C
T
C
T
C
T
T
C
C
5
T
C
A
U
G
N
uo
NNUAG
RF SS
T
O
P
IR
E
S
dan kinetika inhibisi terjemahan keseluruhan tergantung pada tingkat keparahan hipoksia (lihat gambar bagian b).
PKR-seperti ER kinase
m
C
(merembes ) fosforilasi -tergantung dari eukariotik
EIF4E
terjemahanfaktor inisiasi 2 (EIF2) bertanggung jawab untuk penghambatan pada waktu awal, dengan beralih ke
hypophosphorylation dari eukariotik faktor inisiasi 4E
pN
u ORF
AUGNAUG
binding protein 1 (4E-BP1) dan EEF2K selama lagi hipoksia
7
G pp
ap
EIF4G
A
A
A
A
A
A
A
AP
Ao
P
ly A
(AB)
P
Coding urut
m
IRN
A
PBD
N
NGAUNN
exposures14,18,20,40.
Pada tingkat transkrip individu, mRNA efisiensi terjemahan sangat bervariasi. Hal ini dipengaruhi oleh Nature mRNA
penyebaran ini
Ulasan | Kanker dimediasi
oleh EIF4E, EIF4G dan poli (A) -binding protein (PABP), serta dengan unsur-unsur dalam 5 dan 3 daerah belum
diterjemahkan (UTRs). Unsur-unsur ini dapat baik merangsang atau menekan terjemahan dan termasuk topi-struktur,
5 terminal oligopyrimidine saluran (5 puncak), hulu rangka baca terbuka (uORFs), struktur sekunder (SS), situs entri
ribosom intern (IRESS), mengikat protein domain ( PBD), dan poli (A) ekor (lihat gambar bagian c). Unsur-unsur ini
memberi selektivitas translasi dan dengan demikian ikut bertanggung jawab atas ekspresi gen diferensial selama
hipoksia. Spesifisitas translasi juga diatur oleh microRNA (miRNA) menargetkan domain dan hipoksia meregulasi
miRNAs yang berfungsi dengan menghambat terjemahan untuk melindungi terhadap caspase activation105 dan
menyebabkan resistensi terhadap agents106 kemoterapi. Tanggapan angiogenik juga tampaknya mengandalkan
peraturan Mirna, sebagai induksi hipoksia dari mir-210 adalah penting bagi migrasi sel endotel dan pembentukan
structures107 kapiler, sedangkan hipoksia downregulates miRNAs yang mencegah ekspresi faktor angiogenik seperti
VEGFA108. Peraturan hipoksia miRNAs setidaknya sebagian tergantung pada HIF1 (ref 105.109.110). Target
langsung beberapa regulasi translasi Mirna diarahkan selama hipoksia telah muncul, tetapi faktor renovasi vaskular
ephrin A3 adalah salah satu example107.
menyebabkan peningkatan toksisitas akibat insults30-32 ini. Bukti autophagy juga telah diamati di
antara Beclin 1 Beclin 1 dan Bcl2 atau BCL-X
activity37, meskipun jelas
L,yang tidak menghambat diperlukan xenografts31 buruk vascularized serta hewan
dalam semua circumstances36. Fungsional pentingnya model
brain33 iskemik dan myocardium34.
hipoksia diinduksi autophagy mungkin juga tergantung
Meskipun mTORC1 penghambatan oleh rapamycin dan
pada latar belakang genetik tumor, di agen lain khususnya jelas
dapat menginduksi autophagy35, perannya dalam
kerentanan mereka untuk menjalani apoptosis31. Iskemia
hipoksia diinduksi autophagy belum pernah secara langsung
dapat mengaktifkan apoptosis dan autophagy, tetapi hanya
menunjukkan. Namun, BNIP3
(ref 30,32)
dan
sel apoptosis-kekurangan dapat autophagy berkontribusi
AMPK36, protein yang berpotensi mengatur mTORC1
untuk bertahan hidup dengan pencegahan nekrosis. Data ini
juga aktivitas selama hipoksia, keduanya telah melaporkan
menyiratkanbahwa regulasi autophagy selama hipoksia
pengaruh hipoksia diinduksi autophagy. BNIP3 mungkin
mungkin lebih penting dalam kanker stadium lanjut yang
memiliki juga mempengaruhi autophagy dengan menggangguinteraksi
cacatdiperoleh di jalur apoptosis.
SIFAT ULASAN | KANKER VOLUME 8 | November 2008 | 855
ULASAN
ER lumen
Hipoksia
BIP
Sitoplasma
BIP
BIP
BIP
BIP
BIP merembes
ATF6
IRE1
XBP1 pra-mRNA splicing
Golgi translokasi
EIF2
P
AAAA
Pembelahan
terjemahanSelektif mRNA AAAA GADD34
ATF4
XBP1 ATF6?
(IRE1, merembes)
Penghambatan
Pematangan mesin terjemahan mRNA global
(pendamping, oksidoreduktase)
ERAD AutophagyPencegahan
Resolusi(beban protein menurun, meningkatkan
fungsi ER)
(penghapusan mis / protein dilipat dan agregat)
Gambar 3 | Hipoksia mengaktifkan respon protein dilipat (UPR). The retikulum endoplasma (ER) stres sensor PKR-
seperti ER kinase (merembes), inositol-membutuhkan protein 1 (IRE1) dan mengaktifkan faktor transkripsi 6 (ATF6)
diaktifkan selama stres ER melalui hilangnya mengikat BIP (pendamping imunoglobulin berat rantai- protein yang
mengikat) dan / atau melalui interaksi langsung dengan protein yang gagal melipat dan agregat. Hasil aktivasi
merembes aktivitas kinase terhadap eukariotik faktor inisiasi 2 subunit (EIF2), mengakibatkan penghambatan
terjemahan mRNA global. Sebuah respon transkripsi juga terjadi melalui aktivasi tiga faktor transkripsi; ATF4, X-box-
binding protein 1 (XBP1) dan ATF6. Paradoksnya, fosforilasi EIF2 menyebabkan terjemahan selektif ATF4
mengakibatkan upregulation transkripsi dari GADD34 (penangkapan pertumbuhan dan DNA-kerusakan-inducible
gen 34), yang mengarahkan aktivitas fosfatase terhadap EIF2. Aktivasi hasil IRE1 dalam kegiatan endoribonuclease
terhadap XBP1 pra-mRNA dan ekspresi XBP1. Aktivasi hasil ATF6 di translokasi ke aparatus Golgi dan pembelahan
proteolitik untuk menghasilkan kapasitas transactivation. Aktivasi hipoksia dari ATF6 belum secara langsung
ditunjukkan, tetapi mungkin didasarkan pada induksi hipoksia gen ATF6 tergantung seperti BIP55, GRP94 (REF. 54)
dan lain-lain (BGW dan MK, pengamatan tidak diterbitkan). ATF4, XBP1 dan ATF6 menginduksi set tumpang tindih
protein yang meningkatkan kapasitas untuk ER-lokal pematangan protein dan degradasi ER-terkait (ERAD).
Penghambatan terjemahan mRNA global dan meningkatkan fungsi ER berfungsi untuk mencegah stres ER lanjut
dengan mengurangi beban protein dan mencegah agregasi protein. ERAD, serta autophagy, berfungsi untuk
mengatasi stres ER dengan menghapus berpotensi beracun protein yang gagal melipat dan agregat protein. Jalur
molekuler yang menyebabkan autophagy ER-stres-induced tetap tidak diketahui, tetapi bergantung pada merembes
dan / atau IRE1. Dasar untuk bagaimana hipoksia menyebabkan ER stres dan aktivasi UPR belum sepenuhnya
dipahami (BOX 2).
Hipoksia dan respon protein dilipat
disebut UPR yang bertujuan untuk memperbaiki ER
homeostasis atau aktivasi UPR mempengaruhi toleransi hipoksia dan
menginduksi kematian sel (Ulasan di
38
REF.).A number of tumour
growth. The ER has emerged as a cellular com-
conditions can activate the UPR, including changes partment
and signalling that independently that is important mediates for the the survival O
2
sensing and
in glycosylation, redox status, glucose availability, calcium homeostasis and secretory protein load39. In function of
hypoxic cells
(FIG. 3)
. The ER is a special-
recent years, evidence from both the laboratory and ized
organelle for the maturation of proteins that are
the clinic indicates that hypoxia is also a strong activa- destined
for membrane expression or secretion. Under
tor of the UPR. This has led to speculation as to how conditions
of ER stress that affect the ability or capac-
hypoxia might cause ER stress, but the molecular basis ity for
protein maturation, unfolded or misfolded pro-
for UPR activation during hypoxia remains poorly teins
accumulate and activate a signalling programme
understood
(BOX 2)
.
856 | NOVEMBER 2008 | VOLUME 8 www.nature.com/reviews/cancer
REVIEWS
UPR signalling is initiated by three distinct ER
apoptosis in hypoxic regions of the tumour42. Reduced stress
sensors: PERK (PKR-like ER kinase, also known
hypoxia tolerance is also evident in MEFs carrying a as
EIF2AK3), inositol-requiring protein 1 (IRE1) and
serine 51 to alanine knock-in mutation in EIF2 (the ATF6. These
are integral ER membrane proteins that
PERK phosphorylation site) that renders it unable to be signal
luminal stress to the cytosol and the nucleus.
phosphorylated43, or in human tumour cells that over- Hypoxia
causes PERK activation, as evidenced by its
express a dominant-negative PERK allele or a GADD34
autophosphorylation as well as by the phosphorylation
fragment20,42, which leads to EIF2 dephosphoryla- of its main
substrate, EIF2 , on serine 51
(REF. 40)
. This
tion. In tumours, hypoxia is also associated with other is a
surprisingly rapid response, occurring within min-
conditions that can cause ER stress and/or UPR acti- utes when
cells are exposed to anoxic conditions and
vation, such as glucose deprivation, amino acid dep- somewhat
more slowly during more moderate (1%)
rivation and oxidative stress39. Thus, UPR activation hypoxic
exposure14. Similar to what has been observed
may be particularly important in the context of solid in response
to other agents that induce the UPR, EIF2
tumours. phosphorylation is transient during hypoxia14,40,41.
Hypoxia also activates IRE1, as evidenced by its This is due
to a negative feedback loop initiated by
splicing activity against X-box binding protein 1 (XBP1) ATF4-
dependent upregulation of GADD34, the sub- strate-targeting subunit of the protein phosphatase 1
pre-mRNA44, this activity is but not the yet O
well-characterized. 2
dependency and kinetics However, of
holoenzyme, which displays phosphatase activity
disruption of the IRE1-dependent arm of the UPR in against
EIF2 38. Phosphorylation of EIF2 during
XBP1-knockout or XBP1-knockdown cells also results hypoxia
has been observed in a diverse array of cell
in increased apoptosis and decreased clonogenic sur- lines
established from either normal or neoplastic
 vival in response to hypoxia, as well as impaired tumour
tissue20,40.
growth44. In breast cancer, a high ratio of spliced (that PERK
activation is important for survival dur-
is, activated) to unspliced XBP1 is associated with poor ing
hypoxic conditions. Transformed mouse embryo
disease-free survival, possibly reflecting the presence fibroblasts
(MEFs) derived from PERK-knockout mice
of hypoxia45. Activation of the third ER stress sensor undergo
apoptosis when exposed to hypoxia and have
ATF6 by hypoxia has not been directly demonstrated reduced
overall levels of survival as assessed by clo-
but is probable, based on the observation that many of nogenic
assays than their wild-type counterparts40,42.
its transcriptional targets are induced under hypoxic Consistent
with this sensitivity to hypoxia, PERK-
conditions. Taken together, these results demonstrate knockout
tumours grow slower and display more
an important role for the UPR in determining hypoxia tolerance and tumour growth, and the potential for therapeutic
intervention is being explored. Box 2 | Mechanisms of hypoxia-induced endoplasmic reticulum stress
Activation of the endoplasmic reticulum (ER) stress sensors PKR-like ER kinase (PERK), inositol-requiring protein 1
(IRE1) and ATF6 involves dissociation from the chaperone BIP or direct binding to unfolded polypeptides. PERK
phosphorylates the
subunit of eukaryotic initiation factor 2 (EIF2), which participates in the ternary complex (EIF2GTPtRNAMet)
responsible for recruiting the first tRNA to the mRNA start codon. Phosphorylation of EIF2 on serine 51 prevents EIF2
-mediated
The importance of UPR activation in tumorigen- esis and tumour malignancy. Given its importance in mediating cell
survival in response to hypoxia in a diverse array of cell types, one might expect that the UPR would promote
carcinogenesis. However, the UPR influences not only adaptation (and survival) dur- exchange of GDP for GTP and
translation initiation is inhibited. Thus, PERK activation
ing ER stress, but also cell death
through regulation results in inhibition of overall mRNA translation, presumably to relieve the stressed
of apoptotic and other effector
pathways46. There are ER of further protein load38. IRE1 is structurally related to PERK and the only ER stress
recent data suggesting that the UPR
can act as a barrier sensor orthologue in yeast. Activation of IRE1 results in endoribonuclease activity against X-box
binding protein 1 (XBP1) pre-mRNA38. The unconventional splicing of the XBP1 pre-mRNA results in translation of
the transcriptional factor XBP1. Many XBP1-dependent genes are involved in ER protein maturation, including
DNAJB9, protein disulphide isomerase P5 (PDI-P5) and DNAJB11. Others include those involved in ER-associated
degradation, such as EDEM1, EDEM2, DNAJC3 and synoviolin. Activation of the third sensor of ER stress, ATF6,
results in its translocation and cleavage to produce an active transcription factor38. ATF6 transcriptionally
against tumorigenesis by inducing a form of senescence in response to oncogene activation in human primary
melanocytes47. However, definitive experiments to test the requirement of UPR signalling involving any or all of the
sensors of ER stress during carcinogenesis have not been carried out. The importance of these path- ways can best
be evaluated in mouse genetic models of regulates genes containing an ER stress response element in their
promoter,
cancer and these experiments are
currently underway including those encoding ER chaperone proteins such as BIP, GRP94 and calreticulin.
in several groups. Hypoxic
homeostasis40,44. activation However, of ER stress the direct sensors requirement strongly suggests that lack of O
2
perturbs ER obscure. The immediate phosphorylation of EIF2 Little is known about cancer-associated changes
involving PERK, IRE1 or ATF6 that affect the sensi- tivity of UPR activation. However, the cellular con- sequences of
their activation are mediated by four distinct effector pathways that collectively act to alle- viate ER stress and
diminish its toxic effects. Each of these effector pathways can influence the phenotype of hypoxic cells in diverse
ways. The effector pathways include two 'preventative' pathways that mediate inhi- bition of mRNA translation and
induction of protein
NATURE REVIEWS | CANCER VOLUME 8 | NOVEMBER 2008 | 857
for upon O 2
anoxic in ER function exposure remains
suggests a oligosaccharide direct role for O
modifications, 2
in ER protein disulphide maturation, bond involving formation, several isomerization, steps of
quality controls In client vitro, protein O and 2
can export. by supply FAD Any and the of oxidative yeast these ERO1P processes potential and PDI, may to drive
and harbour a disulphide yeast requirements ero1-1 bond mutant formation for O
is
2
.
of a
sensitive acceptor to in hypoxia111. the ER of mammalian It remains to cells be in established vivo, and whether
whether this O 2
is can a crucial account electron
for limited ER function during hypoxia.
REVIEWS
maturation machinery. Together these pathways
upregulation of the protein maturation machinery in function to
prevent further accumulation of unfolded
the ER might also contribute to increased secretion of proteins
in the ER. At the same time UPR-dependent
angiogenic or other factors. Blockade of the UPR through
processes stimulate ER-associated degradation (ERAD)
expression of a dominant-negative IRE1 has been and
autophagy to remove potentially toxic misfolded
shown to reduce VEGFA secretion and result in smaller proteins
or protein aggregates that may have already
tumours with reduced vascular density59. Similarly,
accumulated
(FIG. 3)
.
knockdown of ERO1L decreased the ratio of extra- cellular VEGFA protein to intracellular mRNA levels, Regulation of
(gene-specific) mRNA translation.
at least under normoxic conditions60. Inhibition of overall protein
synthesis has long been known to be a hallmark of hypoxia48. As discussed ear-
Regulation of ER-associated degradation. There is lier, part of
this inhibition is mediated through regu-
strict quality control of protein folding in the ER, lation of EIF4E
through mTOR-influenced pathways.
which is applied before exit to the Golgi. If the bat- However, the
majority of this effect during acute expo-
tery of maturation proteins fails to produce a bona fide sures to
severe hypoxia is due to PERK-dependent phos-
folded protein, the aberrant protein can be targeted for
phorylation of EIF2 14,20,40. As is the case for mTOR,
ERAD, for example, through mannose trimming of inhibition of
translation through PERKEIF2 is
N-linked glycans61. ERAD is an important detoxifica- expected
to affect both energy homeostasis and specific
tion mechanism that prevents protein aggregation and gene
expression during hypoxia
(BOX 1)
. The transcript
cytotoxicity. The importance of ERAD in mediating best
characterized in this respect is that encoding ATF4,
hypoxia tolerance has yet to be investigated, but sev- the 5 UTR
of which contains two conserved upstream
eral proteins involved in ERAD are induced by hypoxia. open
reading frames (uORFs) that prevent efficient
These include HERP (HERPUD1, suggested to link translation
under normal conditions. Reduction in the
client proteins and the proteasome), SEC61A1 (trans-
availability of non-phosphorylated EIF2 reduces ini-
locon subunit)44 and synoviolin (also known as HRD1, tiation at
the second uORF and increases the chance
a ubiquitin ligase)62. Interestingly, valosin-containing that
initiation occurs at the bona fide start codon49,50.
protein (VCP), which is also required for transport Consequently,
ATF4 is induced during acute hypoxia in
of substrate proteins to the proteasome, was found to a PERK
and EIF2 -phosphorylation-dependent man-
translocate from the nuclear-membrane fraction to the ner14,51.
ATF4 is an important transcription factor and
cytoplasm in response to reoxygenation63. This suggests has
been shown to be overexpressed in cancer, primarily
a demand for ERAD to re-establish ER homeostasis in in
hypoxic perinecrotic regions of human tumours52.
the recovery phase following hypoxic stress. Selective synthesis
of ATF4 during hypoxia also appears to be required for maintaining hypoxia tolerance42.
Regulation of autophagy. Growing evidence suggests that
Several other transcripts of relevance to hypoxia are also
autophagy is also influenced by the UPR in response to
selectively translated in a PERK-dependent manner,
ER stress. In some cases autophagy appears to be medi-
including VCIP (VEGF and type I collagen-inducible
ated by PERK whereas in others it occurs downstream protein)
and matrix metalloproteinase 13 (MMP13)53.
of IRE1. For example, aggregation of polyglutamine, These
effects may explain the defects in angiogenesis
associated with Huntington disease, induces UPR and that
contribute to the poor growth of Perk-deficient
autophagic vesicle formation through PERK64, whereas
tumours53.
tunicamycin and thapsigargin require IRE1
(REF. 65)
. In The transient
inhibition of mRNA translation by
yeast, a newly recognized form of autophagy that dis- PERK can
also liberate the translational machinery
plays selectivity for the ER is also activated by IRE1 and
(eukaryotic initiation factors, ribosomes and so on) from
is thought to be important for the removal of protein pre-existing
translation-competent transcripts such that
aggregates that are not substrates for ERAD66,67. The newly
made mRNAs may be able to more effectively
importance of UPR-dependent autophagy mediated by compete
for the translational machinery. This shift in
PERK or IRE1 in response to hypoxia is currently being
translation has been referred to as 'translational repro-
investigated by several groups.
Tunicamycin
gramming'38 and may allow for a bias in the synthesis of A mixture of homologous
antibiotics that prevent N-linked glycosylation of proteins in the ER lumen by inhibiting the enzyme
hypoxia-inducible mRNAs.
Regulation of apoptosis and survival. In addition to these four main effector pathways that serve as tol-
Regulation of protein maturation machinery. Many
erance mechanisms, prolonged ER stress becomes proteins
involved in ER-localized protein folding
toxic, and the UPR can participate in
this by promot- N-acetylglucosamine
and maturation have been reported to be upregu-
ing apoptosis. The pro-apoptotic family
members BAX transferase. As a result, it is a potent inducer of the UPR.
lated during hypoxic conditions. This includes chap-
and Bcl2 homologous antagonist/killer (BAK) associ- erones
such as BIP (also known as GRP78), ORP150
ate with activated IRE1 and are required for signal-
Thapsigargin
and GRP94
(REFS 5456)
ling the transcriptional UPR response
through XBP1 An inhibitor of Ca2+ pumps
activation68. Interestingly, the
transcriptional regula- located in the sarcoplasmic reticulum and ER membranes. Depletion of ER calcium stores
results in the induction of the UPR.
, as well as oxidoreductases such as ERO1L44,57 and PDI58. Although their induc- tion is
predicted to improve ER function during
tor C/EBP homologous protein (CHOP; also known as hypoxia
and potentially mitigate the toxicity associ-
DDIT3), which is induced downstream of both PERK ated with
accumulation of protein aggregates, this
and IRE1, confers increased apoptotic sensitivity to at has not
yet been formally shown. UPR-dependent
least some forms of ER stress69. This may occur through
858 | NOVEMBER 2008 | VOLUME 8 www.nature.com/reviews/cancer
REVIEWS
IRS1 JNK
protein stability and transcriptional activity are directly regulated is also by the availability influenced by signalling of O
2
(REF. pathways 87)
, its involving synthesis
mTOR. Oncogenic mutations that inactivate PTEN,
HIF1
mTOR
ER stress: UPR
PML or TSC1TSC2
(REFS 10,71,72)
, or activate HRAS, ERBB2 or the PI3KAkt pathway cause increased HIF1
HIF1
expression7375 that can be blocked by rapamycin72,75,76. Together with increased HIF1 rates of synthesis and
HIF1
ATF6
PERK a high dependency on the HIF1A 5 UTR10,75, this sug- IRE1
gests that mTOR promotes HIF1 expression through increased rates of mRNA translation, perhaps through a
REDD1
5 terminal oligopyrimidine sequence77. There is also evi- dence that HIF1 interacts directly with the mTORC1 BNIP3
TRAF2
complex member raptor through its mTOR signalling
Figure 4 | Negative feedback loops from hypoxia-inducible factor 1 (HIF1) and unfolded protein response
(UPR) to mammalian target of rapamycin (mTOR). mTOR activity has an influence on HIF1 through its ability
to selectively regulate
motif, and that this is important for HIF1 transcriptional activity78.
It is difficult, however, to reconcile
the idea that translation of the of the HIF1A mRNA transcript. The transcriptional targets of
arguably the most important hypoxic
transcription fac- HIF1, BNIP3 (BCL2/adenovirus E1B 19-kD protein-interacting protein 3) and
tor is dependent on mTOR for its
synthesis and activity, REDD1 also function to inhibit mTOR activity. Deregulation and activation of
as mTOR is inhibited by hypoxia. In
fact, a number of mTOR can cause endoplasmic reticulum (ER) stress, presumably through increased client load in
the ER. Activation of the ER stress sensors inositol-requiring protein 1 (IRE1) can also influence mTOR activity by
recruitment of TRAF2 (tumour necrosis factor receptor associated factor 2) to phosphorylated IRE1. This leads to
JUN N-terminal kinase (JNK)-mediated phosphorylation and inactivation of insulin receptor substrate 1 (IRS1), a
positive regulator of mTOR activity. PERK, PKR-like ER kinase.
reports indicate preferential translation of both murine Hif1a and Vegfa during hypoxic conditions79,80. This might be
due to an internal ribosome entry site in the 5 Hif1a UTR80,81 but this remains controversial, particu- larly for human
HIF1a82,83. Clearly, the mechanisms of mTOR-dependent regulation of HIF1 expression and activity during
normoxia and hypoxia, and its functional consequences, are in need of further investigation.
Conversely, as described above, HIF1 is responsible
transcriptional regulation of CHOP-dependent targets
for at least some of the inhibition of mTORC1 activity such as
ERO1L or GADD34 that also confer tunicamy-
during hypoxia through its ability to upregulate both cin
sensitivity70. As GADD34 expression restores pro-
REDD1 and BNIP3. It is likely that HIF1 regulation of tein
synthesis by causing EIF2 dephosphorylation,
these genes acts to support rather than initiate mTORC1 it
therefore increases the client load of proteins that
inhibition during hypoxia, as hypoxic exposures as short must be
properly folded within the ER. In the con-
as 30 minutes are sufficient to block mTORC1. Under tinued
presence of agents that disrupt protein matu-
these conditions, inhibition of mTORC1 occurs in a ration this
can increase their toxicity70. Induction of
HIF1-independent manner4. ERO1L during ER stress could
potentially catalyse disulphide bonds in the ER and by doing so stabilize
Metabolism. HIF1 and mTOR signalling represent toxic unfolded
protein aggregates. Although the UPR
two of the strongest regulators of cellular metabolism. has been
associated with activation of cell death during
Studies using rapamycin or inactivating mTOR muta- chronic
treatment with agents such as tunicamycin or
tions have identified mTOR as a positive regulator of
thapsigargin, it is not clear whether a similar situation
glycolysis as well as of the biosynthesis of lipids, amino exists
during hypoxia. We predict that hypoxia might
acids, nucleo tides and proteins8486. The HIF transcrip- differ
from other agents and conditions used to study
tion factors are master regulators of glucose metabo- ER stress
in this respect, because mRNA translation
lism during hypoxia (or when deregulated in cancer). remains
inhibited through EIF2 -independent mech-
They target a large number of genes that promote gly- anisms
during prolonged exposures despite expression
colysis while shunting pyruvate to anaerobic metabo-
5' Terminal oligopyrimidine A stretch of nucleotides at the 5' end of the mRNA, consisting of the pyrimidine derivatives
of GADD34. Thus, hypoxia is able to transfer control lism through l-lactate dehydrogenase of translation inhibition
from EIF2 to EIF4E and by
dehydrogenase kinase 1
(REF. 87) doing so both maintain a low
overall rate of protein synthesis and yet alter the range of selectively translated
A and pyruvate
cytosine and uracil. These
proteins. sequences are present in the mRNA of some ribosomal proteins and translation
factors and confer extreme
Interplay between mTOR, UPR and HIF mRNA translation. A number of interesting potential responsiveness to
positive and
connections have emerged between HIF and mTOR and negative growth signalling in terms
of translation efficiency. The sequence requirements
. HIF1 can also antago- nize cellular respiration by promoting mitochondrial degradation
through BNIP3-dependent autophagy32 as well as inhibiting MYC activity and preventing mito- chondrial
biogenesis88. The interplay between HIF1 and MYC, another transcriptional regulator of metabolism, has recently
emerged as an area of interest (reviewed in REFS 8991
). HIF1 negatively regulates MYC through there are
clear examples of these pathways regulating
multiple mechanisms, including promoting protea- each other
and common downstream pathways
(FIG. 4)
somal degradation of MYC88, transcriptional upregula-
and molecular mechanism are not well understood.
. Perhaps the most firmly established is the ability of
tion of the MYC antagonist MAX-interacting protein 1 mTOR to
influence HIF1A translation. Although HIF1
(MXI1)92, as well as repressing MYC transcriptional
NATURE REVIEWS | CANCER VOLUME 8 | NOVEMBER 2008 | 859
REVIEWS
Box 3 | Hypoxia-modifying cancer treatments
The adverse effect of hypoxia on treatment response was recognized more than 50 years ago112 and many attempts
to modify oxygenation or its impact have been explored clinically (reviewed in REF. 113). Bioreductive drugs such as
tirapazamine114, which become selectively toxic to hypoxic cells due to a one-electron reduction in a hypoxic
environment, represent an alternative approach that has failed so far owing largely to drug-associated toxicities.
Tumour hypoxia is also relevant for the use and evaluation of many molecular targeted agents. A number of attempts
have been made to target the hypoxia-inducible factor (HIF) pathway through direct inhibition of HIF itself or its
downstream effectors such as vascular endothelial growth factor (VEGFA; reviewed in REF. 115). More recent
elucidation of the unfolded protein response (UPR) and mammalian target of rapamycin (mTOR) as mediators of
hypoxia tolerance has stimulated similar efforts to target these pathways and their downstream effectors. Although
identification of such agents is still ongoing, many current molecular targeting agents have been reported to influence
(or be influenced by) these signalling pathways. This is certainly true for the large number of kinase inhibitors and
antibodies targeting upstream components of mTOR signalling. These agents will undoubtedly show differential
activity in hypoxic and non-hypoxic parts of individual tumours that have different reliance on mTOR. For example,
inhibition of mTORC1 may increase tumour hypoxia and tumour resistance to treatment116 by inhibiting
angiogenesis or by promoting thrombosis117. Furthermore, these agents, by influencing mTOR and UPR signalling,
may also interfere with hypoxia sensing pathways and thus affect the tumour microenvironment itself. In this regard it
is interesting to note that a large number of the agents that have demonstrated clinical value influence hypoxic cell
signalling and improve tumour oxygenation (see table). This may occur in part through decreased VEGFA expression
and normalization of tumour vasculature118, although many other unexplored possibilities could equally be
responsible. A good example of an agent that affects hypoxia sensing and signalling is the HIV drug nelfinavir, which
is under evaluation in cancer trials. It is a protease inhibitor that has been shown to cause endoplasmic reticulum
(ER) stress119,120, inhibit Akt signalling121, impair HIF1 and VEGFA expression122, and induce apoptosis and
autophagy123. The combined effects of nelfinavir result in significant alteration of the tumour microenvironment, with
less tumour hypoxia and increased radiation response121,122. The table shows a selection of anticancer agents that
are currently clinically available or in cancer trials that affect signalling through mTOR and/or the UPR, and
simultaneously alter the tumour microenvironment. A number of other interesting agents in the clinic target pathways
that are downstream effectors of the UPR and mTOR signalling, including bevacizumab (angiogenesis) and
hydroxychloroquine (autophagy). The clinical efficacy of these agents is expected to influence or be influenced by
tumour hypoxia and in several cases this has been demonstrated.
Agent Molecular target(s) Hypoxia Angiogenesis Refs Signalling to mTOR Cetuximab (C225) EGFR NA
124,125
Trastuzumab ERBB2 126,127
Gefitinib EGFR 128131
Imatinib BCRABL1, KIT, PDGFR 132
Sorafenib Raf, Erk, VEGFRs, PDGFR 133
Rapamycin analogues mTOR NA 134136
Tipifarnib HRAS 137,138
Signalling through UPR pathway (causes ER stress)
Bortezomib 26S proteasome NA 139142
Nelfinavir 26S proteasome 122,143
17-AAG (geldanamycin) HSP90, GRP94 NA 144,145
Arrows indicate the effect the agents have on the level of tumour hypoxia, as assessed by hypoxic cell markers, and
on angiogenesis, assessed by, for example, vessel sprouting or density. BCR, breakpoint cluster region protein;
EGFR, epidermal growth factor receptor; Erk, extracellular-signal-regulated kinase; GRP, glucose-regulated protein;
HSP, heat-shock protein; NA, not assessed; PDGFR, platelet-derived growth factor receptor.
activity93. Strikingly, HIF2 seems to function in an
between these pathways will undoubtedly lead to new opposite
manner to promote MYC transcriptional activ-
insights into tumour biology and opportunities for ity and
proliferation during hypoxia93, but is nonetheless
exploiting altered metabolism in cancer89. required for hypoxia-
induced transcriptional upregula- tion of MXI1
(REF. 88)
. Clearly, these data indicate that
Autophagy. There is evidence that activation of MYC, mTOR
and HIF collaborate in both synergistic
autophagy is sensitive to hypoxic signalling through and
antagonistic ways to regulate cellular metabolism
HIF, mTOR and UPR pathways. The fact that all three
downstream of some of the most common mutations
of these pathways independently signal to autophagy in cancer.
A better understanding of the intersection
suggests this response may be a particularly important
860 | NOVEMBER 2008 | VOLUME 8 www.nature.com/reviews/cancer
REVIEWS
effector of hypoxia tolerance. Indeed, in an elegant
The relative importance of HIF, mTOR and UPR series of
experiments, White and colleagues have dem-
During the course of this Review, we have discussed onstrated
that autophagy has a key role during tumour
a number of studies that suggest important roles for
development by responding to metabolic stress that
the mTOR and UPR pathways in the determination includes
exposure to hypoxia94,95. ER stress and hypoxia-
of hypoxic cell phenotype, hypoxia tolerance and induced
autophagy may also be linked to the mTOR
tumour growth. These add to the well-established pathway
through changes in cytoplasmic calcium lev-
role of HIF1 in cancer progression and hypoxia els. Hypoxia
increases cytoplasmic influx and ER efflux (reviewed in
REF. 96
), which can stimulate AMPK acti-
responses103. pathways in mind, With these how should major we O 2
-sensitive evaluate their response rela- vation through calciumcalmodulin-dependent kinase
tive importance in human cancer? It is clear that they kinase 2
(CAMKK2), resulting in mTOR inactivation and autophagy97. Furthermore, Ca2+ release from the
show and on unique duration dependencies of exposure. both The on highly O
2
concentration heterogene- ER activates members of the protein kinase C (PKC)
ous and dynamic tumour microenvironment produces family,
and a recent report showed that PKC is phos-
many types of hypoxia, which differ in severity and phorylated in
a PERK- and IRE1-independent manner
duration1. Consequently, tumours consist of hypoxic in response
to ER stress-related calcium efflux. PKC
subpopulations that rely on different hypoxic response
expression was necessary for activation of autophagy
pathways at different times. It is poorly understood as assessed
by LC3B98. Although PKCs are inhibitors of
which cell populations limit tumour curability or are PI3K and
hence of mTOR activity, this has not formally
responsible for specific adverse phenotypes such as been
shown to affect mTOR-dependent autophagy.
metastasis. Is it the chronically and moderately hypoxic
ER homeostasis. A number of links between mTOR, HIF, the UPR and ER homeostasis have also begun
(12% it the populations O 2 ) cells that that are experience present for rapid a long and time, severe fluctuations that
 approach anoxia? Our ability to or is pre- O
2
to emerge. The IRE1-dependent activation of JUN N-terminal kinase has not only been tied to apoptosis
dict in determining the importance treatment of O 2 response -sensing response is currently pathways limited and
autophagy, but also appears to have an important
by our understanding of the relative contributions of role in the
response to insulin signalling and its ability
these cell populations to outcome. Consequently, in to regulate
mTOR. JUN N-terminal kinase activation
the future it will be important to investigate to what by ER stress
results in phosphorylation and inactiva-
extent each of these three pathways is responsible for tion of
insulin receptor substrate 1 (IRS1), and this can
the poor prognosis that is associated with hypoxia in contribute
to insulin resistance and reduced PI3K and
human tumours. mTOR activity99. Conversely, loss of mTORC1
regula-
This question is of particular interest as we progress tion in
cells lacking Tsc1 or Tsc2 causes activation of
towards molecular cancer therapeutics that are influ- the ER
stress sensors PERK and IRE1
(REF. 100)
. The ER
enced by hypoxic signalling or that are specifically stress
resulting from mTORC1 deregulation might be
designed to target hypoxic responses
(BOX 3)
. Much a result of
inappropriate mRNA translation and exces-
of our current knowledge in this area is derived sive demands
for protein folding. These results dem-
from experiments comparing the growth of tumour onstrate the
existence of multiple negative feedback
xenografts derived from knockout and knock-in loops between
the mTOR and the UPR pathways. The
MEFs or genetically modified tumour cell lines in importance of
this connection has not been explored
which the pathway of interest (for example, HIF and during
hypoxia, and we await the results from such
PERK) is disrupted. Although these experiments pro-
investigations with interest. The frequent activating
vide valuable mechanistic insight into the functions genetic
alterations of the mTOR pathway in cancer may
of these pathways and their influences on tumour thus also have
a profound impact on UPR-dependent
growth, they do not adequately address the potential responses
to hypoxia.
for members of these pathways as molecular targets There also
appears to be some transcriptional coop-
in cancer therapy. During the course of tumour estab- eration
between HIF and UPR responses to hypoxia.
lishment and growth in these model systems, adap- As
discussed earlier, ERO1L, which is important for
tation and compensation undoubtedly take place in disulphide
bond formation and protein folding in the
ways that significantly alter the tumour microenviron- ER, is
transcriptionally induced by both HIF and the
ment and its phenotype. There is a need for experi-
UPR57,60,70,101. HIF-mediated upregulation of ERO1L
ments to determine whether (genetic) disruption of appears to
aid in synthesis and secretion of VEGFA.
UPR, HIF or mTOR pathways provides a therapeu- Similarly we
have recently found that carbonic anhy-
tic benefit when applied to established tumours and drase 9, an
important regulator of tumour pH, is also
in combination with other treatment modalities jointly regulated
by both ATF4 and HIF1 (T. van den
that are aimed at killing non-hypoxic cells. A com- Beucken et
al., unpublished observations). It will be
mon challenge for the future is thus to provide better important
to examine whether this cooperative regula-
understanding not only of the balance between the tion extends
to other HIF and UPR targets. Curiously,
interrelated network of hypoxia response pathways, ATF4, which
is translationally induced during the UPR,
but also to determine the points within these path- is also
stabilized during hypoxia by a mechanism similar
ways that make hypoxic tumours most vulnerable to to HIF1
102.
molecular targeting.
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We wish to acknowledge the
excellent work and contribu- epidermal growth factor receptor (EGFR) to EGFR-
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metalloproteinase 2 expression in human glioma
studies received financial support
from the Dutch Science overexpressing breast cancer xenograft models with
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Organization (ZonMW-NWO Top
grant 912-03-047 to trastuzumab (Herceptin) and gefitinib (ZD1839): drug
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DATABASES National Cancer Institute: http://www.cancer.gov/ breast cancer National Cancer Institute Drug
Dictionary: http://www. cancer.gov/drugdictionary/ nelfinavir | rapamycin | tirapazamine OMIM:
http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?db=OMIM Huntington disease | PeutzJeghers syndrome | tuberous
sclerosis syndrome UniProtKB: http://www.uniprot.org 4E-BP1 | 4E-T | ATF4 | ATF6 | ATG5 | BAD | BAK | BAX | BCL2
| BCL-X
L temsirolimus. Kanker
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rhabdomyosarcoma
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antiangiogenic mechanism
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mTOR/Hif-1 /VEGF signaling.
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Bevacizumab and
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Kanker Res. 62, 24782482 (2002).
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