ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth

Abstract

Tumor cell adaptation to hypoxic stress is an important determinant of malignant progression. While much emphasis has been placed on the role of HIF-1 in this context, the role of additional mechanisms has not been adequately explored. Here we demonstrate that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR), which adapts cells to endoplasmic reticulum (ER) stress. Inactivation of ISR signaling by mutations in the ER kinase PERK and the translation initiation factor eIF2a or by a dominant-negative PERK impairs cell survival under extreme hypoxia. Tumors derived from these mutant cell lines are smaller and exhibit higher levels of apoptosis in hypoxic areas compared to tumors with an intact ISR. Moreover, expression of the ISR targets ATF4 and CHOP was noted in hypoxic areas of human tumor biopsy samples. Collectively, these findings demonstrate that activation of the ISR is required for tumor cell adaptation to hypoxia, and suggest that this pathway is an attractive target for antitumor modalities.

The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors

“…A critical role for PERK-mediated translational control in hypoxia survival is further substantiated by results from mouse embryonic fibroblasts expressing a ''knock-in'' mutant allele of eIF2a (S51A) that cannot be phosphorylated by PERK. These cells exhibit an increased susceptibility to hypoxia, with virtually no survival after a 48-hour exposure compared with a 40% survival rate for cells expressing wild-type eIF2a (82). Importantly, impairment of PERK signaling in HT29 colorectal carcinoma cells causes increased apoptosis following hypoxia and significantly attenuates the growth of subcutaneously implanted tumor xenografts.…”

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

“…depletion [56][57][58]. Therefore, we hypothesized that miR-214 may also directly target ATF4 to initiate the protective mechanism in erythroid cells in response to oxidative stress.…”

Targeting Translation in Hypoxic Tumors

“…A clue was provided by the finding that ischemia and the attendant hypoxia and nutrient deprivation activate PERK (9,10 ), an eIF2α kinase that responds specifically to the stress of unfolded and misfolded proteins in the endoplasmic reticulum (ER stress) (11 ). The mechanism(s) by which hypoxia elicits ER stress and PERK activation remain obscure; however, the importance of PERK activation and eIF2(αP) to translational control in hypoxic cells is well documented by analysis of PERK -/-cells and cells bearing a Ser51 to Ala mutation in the regulatory residue of eIF2α (12 ). This adaptation to hypoxia has proven to promote survival of cancer cells in ischemic animal tumor models, as cancer cells compromised in their ability to effect eIF2α phosphorylation in response to hypoxia were compromised in their ability to proliferate and form large, A B S T R A C T Recent insight into how mammalian cells adapt their translational machinery to hypoxic conditions raises the possibility of targeting components of the regulatory networks involved to selectively inhibit metabolically compromised tumor cells and possibly manipulate a broad range of other physiological processes.…”

“…w w w. a c s c h e m i ca l biology.org ischemic tumors (12 ). The adaptive role of eIF2α phosphorylation is likely played out both at the level of its global affects on protein synthesis in hypoxic cells and through the induction of a cytoprotective gene expression program, known as the integrated stress response, which is activated by translationally controlled eIF2(αP)-dependent transcription factor(s) such as ATF4 (13 ) (Figure 1).…”

“…The role of eIF2(αP) in promoting the survival of hypoxic tumor cells is supported by genetic experiments (12 ); the contribution of hypoxia-mediated inhibition of eIF4F is less clear. Experiments in flies show that mutations compromising the ability to repress TOR and promote the regulated dephosphorylation of 4EBPs sensitize animals to hypoxia (14 ).…”