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Open AccessArticle

Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells

1
Department of Biochemistry, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City 04510, Mexico
2
Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Mexico City 04510, Mexico
3
Immunology unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
4
Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(6), 755; https://doi.org/10.3390/cancers11060755
Received: 16 April 2019 / Revised: 17 May 2019 / Accepted: 20 May 2019 / Published: 30 May 2019
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
Hypoxia and the accumulation of hypoxia-inducible factors (HIFs) in tumors have been associated with therapeutic resistance and with autophagy establishment. We examined the effects of stable knockdown of HIF-1α or HIF-2α expression on autophagy and drug resistance in colon cancer cells. We found that under normoxic conditions, malignant cells exhibit increased basal levels of autophagy, compared with non-malignant cells, in addition to the previously reported coexpression of HIF-1α and HIF-2α. Knockdown of HIF-1α or HIF-2α expression resulted in increased autophagic and apoptotic cell death, indicating that the survival of cells is HIF-dependent. Cytotoxic-induced cell death was significantly increased by knockdown of HIFs but not by autophagy inhibition. Strikingly, although malignancy-resistant cells were sensitized to death by nutrient stress, the combination with HIF-2α depletion, but not with HIF-1α depletion, induced severe cell death. Oxidative stress levels were significantly increased as a result of HIF-2α specific inhibition or silencing suggesting that this may contribute to sensitize cells to death. The in vitro results were confirmed in vivo using a xenograft mouse model. We found that coordinated autophagy and mTOR inhibition enhanced cell death and induced tumor remission only in HIF-2α-silenced cells. Finally, using a specific HIF-2α inhibitor alone or in combination with drugs in patient-derived primary colon cancer cells, overcame their resistance to 5-FU or CCI-779, thus emphasizing the crucial role played by HIF-2α in promoting resistance and cell survival. View Full-Text
Keywords: colon cancer; hypoxia-inducible factors; drug resistance; autophagy colon cancer; hypoxia-inducible factors; drug resistance; autophagy
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Saint-Martin, A.; Martínez-Ríos, J.; Castañeda-Patlán, M.C.; Sarabia-Sánchez, M.A.; Tejeda-Muñoz, N.; Chinney-Herrera, A.; Soldevila, G.; Benelli, R.; Santoyo-Ramos, P.; Poggi, A.; Robles-Flores, M. Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells. Cancers 2019, 11, 755.

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