Hypoxia signalling through mTOR and the unfolded protein response in cancer

Abstract

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.