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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

Open Access 01-12-2021 | Review

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

Authors: Muhlis Akman, Dimas Carolina Belisario, Iris Chiara Salaroglio, Joanna Kopecka, Massimo Donadelli, Enrico De Smaele, Chiara Riganti

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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Abstract

Solid tumors often grow in a micro-environment characterized by < 2% O2 tension. This condition, together with the aberrant activation of specific oncogenic patwhays, increases the amount and activity of the hypoxia-inducible factor-1α (HIF-1α), a transcription factor that controls up to 200 genes involved in neoangiogenesis, metabolic rewiring, invasion and drug resistance. Hypoxia also induces endoplasmic reticulum (ER) stress, a condition that triggers cell death, if cells are irreversibly damaged, or cell survival, if the stress is mild.
Hypoxia and chronic ER stress both induce chemoresistance. In this review we discuss the multiple and interconnected circuitries that link hypoxic environment, chronic ER stress and chemoresistance. We suggest that hypoxia and ER stress train and select the cells more adapted to survive in unfavorable conditions, by activating pleiotropic mechanisms including apoptosis inhibition, metabolic rewiring, anti-oxidant defences, drugs efflux. This adaptative process unequivocally expands clones that acquire resistance to chemotherapy.
We believe that pharmacological inhibitors of HIF-1α and modulators of ER stress, although characterized by low specificty and anti-cancer efficacy when used as single agents, may be repurposed as chemosensitizers against hypoxic and chemorefractory tumors in the next future.
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Metadata
Title
Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons
Authors
Muhlis Akman
Dimas Carolina Belisario
Iris Chiara Salaroglio
Joanna Kopecka
Massimo Donadelli
Enrico De Smaele
Chiara Riganti
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-020-01824-3

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