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HIF-1α-dependent autophagy protects HeLa cells from fenretinide (4-HPR)-induced apoptosis in hypoxia.
- Source :
-
Pharmacological research [Pharmacol Res] 2010 Nov; Vol. 62 (5), pp. 416-25. Date of Electronic Publication: 2010 Jul 15. - Publication Year :
- 2010
-
Abstract
- Novel therapeutic strategies are needed to address and to solve the emerging problem of hypoxia-induced resistance to anticancer drugs. N-(4-Hydroxyphenyl)retinamide (4-HPR) exhibits potent anticancer and chemopreventive activities, but its inefficiency under hypoxia, through undetermined mechanisms, may contribute to its lack of activity in clinical trials. In this study, we showed that under normoxia, 4-HPR resulted in apoptosis and ultimate cell death; in contrast, under hypoxia, autophagy was preferentially induced by 4-HPR at an equivalent concentration, accompanied by microtubule associated protein light-chain 3 (LC3) conversion and acidic vesicular organelle formation. Under hypoxia, autophagy inhibition by 3-methyladenine or chloroquine significantly enhanced apoptosis and decreased cell viability in 4-HPR-exposed cells, indicating that autophagy prevents cancer cell death and presumably leads to hypoxia-induced resistance to 4-HPR. Importantly, knockdown of hypoxia-inducible factor-1α (HIF-1α) inhibited autophagy but promoted 4-HPR-induced apoptosis under hypoxia, demonstrating its critical role as a mediator of this protective autophagy. The present study provides the first evidence supporting the hypothesis that autophagy and apoptosis can be differentially induced by 4-HPR under different oxygen conditions; mediated by HIF-1α, 4-HPR-induced autophagy under hypoxia confers a survival advantage to HeLa cells, protects them from 4-HPR-induced death signals, and thus contributes to their hypoxia-induced resistance to this agent. Our data suggest that autophagy inhibition is a potential alternative strategy to overcome hypoxia-induced resistance to 4-HPR and enhance the anticancer activities of this agent.<br /> (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Subjects :
- Antineoplastic Agents metabolism
Cell Death
Cell Line, Tumor
Cell Survival drug effects
Drug Resistance, Neoplasm
Female
Fenretinide metabolism
HeLa Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Antineoplastic Agents pharmacology
Apoptosis drug effects
Autophagy drug effects
Cell Hypoxia
Fenretinide pharmacology
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1096-1186
- Volume :
- 62
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Pharmacological research
- Publication Type :
- Academic Journal
- Accession number :
- 20637870
- Full Text :
- https://doi.org/10.1016/j.phrs.2010.07.002