The paradoxical role of ER stress in malignant diseases is only just being unraveled
and remains incompletely understood. A particular challenge is the complex interplay between
spaciotemporal and locoregional microenvironmental constraints in solid tumors and
stress responses upon treatment; thus, the potential for new combinatorial therapeutic options
to foster the coincidence of ER stress-related deadly events is likely to be underestimated.
Without claiming this review to be complete, we present a comprehensive overview of the
signaling mechanisms associated with the unfolded protein response (UPR) and the molecular
link to cell survival and death mechanisms. We (i) delineate the mechanistic scenario and outcome
of the UPR; (ii) discuss the role of ER stress in cancer development and progression;
(iii) highlight the impact of various environmental conditions and stress stimuli, such as nutrient
limitation and tumor hypoxia, in this context; and (iv) attempt to shed some light on the
putative link between DNA damage, irradiation, and ER stress to emphasize the potential of
therapeutic targeting of ER stress pathways for combined cancer treatments.
Keywords: Endoplasmic reticulum stress, unfolded protein response, cancer cell, tumorigenesis, microenvironment,
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