Hypoxia is a major hallmark of the tumor microenvironment that is strictly 
associated with rapid cancer progression and induction of metastasis. Hypoxia 
inhibits disulfide bond formation and impairs protein folding in the Endoplasmic 
Reticulum (ER). The stress in the ER induces the activation of Unfolded Protein 
Response (UPR) pathways via the induction of protein kinase RNA-like endoplasmic 
reticulum kinase (PERK). As a result, the level of phosphorylated Eukaryotic 
Initiation Factor 2 alpha (eIF2α) is markedly elevated, resulting in the 
promotion of a pro-adaptive signaling pathway by the inhibition of global 
protein synthesis and selective translation of Activating Transcription Factor 4 
(ATF4). On the contrary, during conditions of prolonged ER stress, pro-adaptive 
responses fail and apoptotic cell death ensues. Interestingly, similar to the 
activity of the mitochondria, the ER may also directly activate the apoptotic 
pathway through ER stress-mediated leakage of calcium into the cytoplasm that 
leads to the activation of death effectors. Apoptotic cell death also ensues by 
ATF4-CHOP- mediated induction of several pro-apoptotic genes and suppression of 
the synthesis of anti-apoptotic Bcl-2 proteins. Advancing molecular insight into 
the transition of tumor cells from adaptation to apoptosis under hypoxia-induced 
ER stress may provide answers on how to overcome the limitations of current 
anti-tumor therapies. Targeting components of the UPR pathways may provide more 
effective elimination of tumor cells and as a result, contribute to the 
development of more promising anti-tumor therapeutic agents.