The development of chronic and fluctuating hypoxic regions in
tumors has profound consequences for malignant progression, response to
therapy and overall patient survival. Understanding the events involved in
hypoxia tolerance will offer new opportunities for antitumor modalities. A universal response of
tumor cells to
hypoxia is a rapid and substantial decrease in the rates of macromolecular synthesis.
Hypoxia induces phosphorylation of the translation
initiation factor eIF2alpha on Ser51 via activation of the endoplasmic reticulum (ER) resident
kinase PERK and that this modification is required for the rapid downregulation of global
protein synthesis by this hypoxic stress. PERK-dependent phosphorylation of eIF2alpha is one component of the Unfolded Protein Response (UPR), a coordinated program that promotes cell survival under conditions of ER stress. Inactivation of PERK or eIF2alpha phosphorylation impairs cell survival under
hypoxia, and transformed cells with inactivating PERK or eIF2alpha mutations form
tumors in nude mice that are slower growing, and have higher levels of apoptosis in hypoxic areas compared to
tumors with an intact UPR. Expression of the
transcription factor ATF4, a downstream effector of eIF2alpha phosphorylation, is also upregulated by
hypoxia in vitro and in human
tumors and increases
hypoxia tolerance. A second UPR pathway mediated by activation of IRE1 and its downstream target XBP1 is also required for
hypoxia tolerance in vitro and for
tumor growth. These results reveal a critical role for UPR activation for
tumor cell resistance to
hypoxia and
tumor growth promotion and suggest that the UPR may be an attractive target for anti-
tumor modalities.