The Mammalian Unfolded Protein Response: A Potential Source of Novel Therapeutic Targets in the Hypoxic Tumour Fraction

Brandon Sit

Abstract


Low oxygenation (hypoxia) in solid cancers contributes to tumour resistance to standard treatment and correlates strongly with negative patient prognoses. Hypoxia activates the mammalian unfolded protein response (UPR), an ER-localized signaling program that regulates transcription and translation in response to an accumulation of misfolded polypeptides. In cancer, UPR signaling is known to be active and important in at least enabling cells to survive hypoxia. The UPR is also hypothesized to play a role in carcinogenesis. The UPR signals through three ER transmembrane sensors, each with their own respective downstream pathways. Depending on the stress input, UPR signaling may result in one of two outcomes – cell adaptation to stress, or apoptosis. While each separate pathway is well studied, few efforts have been made to integrate them to assess their relative importance in contributing to either outcome. This review provides an overview of the current understanding of UPR signaling under hypoxia and highlights an as-yet incompletely understood question of whether the UPR can be artificially manipulated to preferentially signal towards one output, potentially acting as a novel therapeutic target in the hypoxic tumour fraction.

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© University of Toronto Journal of Undergraduate Life Sciences.