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
Keywords: Tumor, PERK, eIF2α, Unfolded Protein Response, ER stress, CHOP, apoptosis.
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