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  • Review Article
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Hypoxia signalling through mTOR and the unfolded protein response in cancer

Nature Reviews Cancer volume 8, pages 851–864 (2008)Cite this article

Key Points

  • Cellular responses to hypoxia are mediated by both hypoxia-inducible factor (HIF)-dependent and HIF-independent pathways. Each of these O2-sensitive signalling pathways exhibits unique sensitivity to the severity and duration of O2 deprivation.

  • Hypoxia inhibits signalling downstream of the kinase mammalian target of rapamycin (mTOR) and mRNA translation initiation through multiple independent mechanisms. Signalling through this pathway appears to influence both tumour progression and hypoxia tolerance in advanced tumours.

  • Severe hypoxic exposure causes endoplasmic reticulum (ER) stress and leads to rapid activation of the unfolded protein response (UPR). The UPR regulates several downstream effector pathways that together function to promote hypoxia tolerance.

  • Hypoxic signalling through mTOR and the UPR results in significant changes in mRNA translation that influence gene expression and cellular behaviour in hypoxic cells. Targeting these pathways can reduce or slow tumour growth.

  • Many of the cellular consequences of hypoxia are jointly influenced by overlapping O2-sensitive pathways. HIF, mTOR and UPR signalling during hypoxia influence tumour metabolism, autophagy and ER homeostasis.

  • Many current and experimental anticancer agents cause ER stress and activate the UPR, and may thus show selective toxicity to hypoxic cells. Conversely, hypoxic signalling through the mTOR pathway is likely to influence the efficacy of many of the new drugs targeting this pathway.

Abstract

Hypoxia occurs in the majority of tumours, promoting angiogenesis, metastasis and resistance to therapy. Responses to hypoxia are orchestrated in part through activation of the hypoxia-inducible factor family of transcription factors (HIFs). Recently, two additional O2-sensitive signalling pathways have also been implicated: signalling through the mammalian target of rapamycin (mTOR) kinase and signalling through activation of the unfolded protein response (UPR). Although they are activated independently, growing evidence suggests that HIF-, mTOR- and UPR-dependent responses to hypoxia act in an integrated way, influencing each other and common downstream pathways that affect gene expression, metabolism, cell survival, tumorigenesis and tumour growth.

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Figure 1: Cellular O2-sensing pathways.
Figure 2: Inhibition of mammalian target of rapamycin (mTOR) signalling by hypoxia.
Figure 3: Hypoxia activates the unfolded protein response (UPR).
Figure 4: Negative feedback loops from hypoxia-inducible factor 1 (HIF1) and unfolded protein response (UPR) to mammalian target of rapamycin (mTOR).

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Acknowledgements

We wish to acknowledge the excellent work and contributions from all members of our teams in both Toronto and Maastricht. We also wish to thank C. Koumenis for our ongoing productive and stimulating collaboration. These studies received financial support from the Dutch Science Organization (ZonMW-NWO Top grant 912-03-047 to BW and VENI grant 916.56.015 to M.K.), the Dutch Cancer Society (KWF grant UM 2003-2821 to B.W.), and the EU 6th framework programme (Euroxy programme to B.G.W.).

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Authors and Affiliations

  1. Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada

    Bradly G. Wouters & Marianne Koritzinsky

  2. Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada

    Bradly G. Wouters & Marianne Koritzinsky

  3. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Bradly G. Wouters

  4. Selective Therapeutics Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada

    Bradly G. Wouters

  5. Maastricht Radiation Oncology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands

    Bradly G. Wouters & Marianne Koritzinsky

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Correspondence to Bradly G. Wouters.

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DATABASES

National Cancer Institute

breast cancer

National Cancer Institute Drug Dictionary

nelfinavir

rapamycin

tirapazamine

OMIM

Huntington disease

Peutz–Jeghers syndrome

tuberous sclerosis syndrome

Glossary

Rapamycin

An antifungal macrolide produced by bacteria, commonly used to prevent post-transplantation organ rejection owing to its immunosuppressive action. Rapamycin binds FKBP12, which in turn binds and inhibits mTORC1.

Autophagy

Literally, “self eating”, autophagy is a process by which cellular components are captured, degraded and recycled using the lysosomal machinery. It is the only cellular process that can degrade covalently linked protein complexes and organelles.

Protein maturation

Maturation of secreted or membrane-destined proteins typically involves N-linked glycosylation during co-translational import to the ER, as well as glycan modification, oxidative folding and isomerization due to disulphide bond formation within the ER lumen. Chaperones accompany the proteins to aid folding and prevent aggregation. Strict quality control is applied before protein release from the folding machinery and export to the Golgi.

Hypoxic phenotype

Characterized by adaptive responses such as decreased proliferation and protein synthesis, high rates of glycolysis and anaerobic metabolism, increased secretion of angiogenic factors and increased metastatic potential. These, together with susceptibility to death pathways, ultimately determine hypoxia tolerance.

mTOR complex 1

(mTORC1). One of two protein complexes (along with mTORC2) known to harbour mTOR. mTORC1 contains mTOR, mLST8, PRAS40 and raptor. Its activation stimulates protein synthesis and cell growth through phosphorylation of p70S6K, 4E-BP and EEF2K.

TSC1–TSC2 complex

This complex of the tumour suppressors TSC1 and TSC2, also known as hamartin and tuberin, respectively, displays GTPase-activating protein activity towards RHEB, resulting in negative regulation of mTORC1. Its activity is negatively regulated by Akt and Erk-mediated phosphorylation of TSC2, and positively regulated by AMPK-dependent TSC2 phosphorylation.

Cap-dependent translation

The main mode of mRNA translation initiation that relies on recruitment of the small ribosomal subunit and associated factors via the 5′ cap structure of the mRNA. This requires binding of the EIF4F complex at the cap, which acts as a scaffold for the ribosomal complex.

Hamartomas

Benign tumours that may cause symptoms due to their location and size.

Tunicamycin

A mixture of homologous antibiotics that prevent N-linked glycosylation of proteins in the ER lumen by inhibiting the enzyme N-acetylglucosamine transferase. As a result, it is a potent inducer of the UPR.

Thapsigargin

An inhibitor of Ca2+ pumps located in the sarcoplasmic reticulum and ER membranes. Depletion of ER calcium stores results in the induction of the UPR.

5′ Terminal oligopyrimidine

A stretch of nucleotides at the 5′ end of the mRNA, consisting of the pyrimidine derivatives cytosine and uracil. These sequences are present in the mRNA of some ribosomal proteins and translation factors and confer extreme responsiveness to positive and negative growth signalling in terms of translation efficiency. The sequence requirements and molecular mechanism are not well understood.

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Wouters, B., Koritzinsky, M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer 8, 851–864 (2008). https://doi.org/10.1038/nrc2501

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