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

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 th...

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Autores principales: Saint-Martin, Abril, Martínez-Ríos, Jacobo, Castañeda-Patlán, M. Cristina, Sarabia-Sánchez, Miguel Angel, Tejeda-Muñoz, Nydia, Chinney-Herrera, Alberto, Soldevila, Gloria, Benelli, Roberto, Santoyo-Ramos, Paula, Poggi, Alessandro, Robles-Flores, Martha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627604/
https://www.ncbi.nlm.nih.gov/pubmed/31151160
http://dx.doi.org/10.3390/cancers11060755
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author Saint-Martin, Abril
Martínez-Ríos, Jacobo
Castañeda-Patlán, M. Cristina
Sarabia-Sánchez, Miguel Angel
Tejeda-Muñoz, Nydia
Chinney-Herrera, Alberto
Soldevila, Gloria
Benelli, Roberto
Santoyo-Ramos, Paula
Poggi, Alessandro
Robles-Flores, Martha
author_facet Saint-Martin, Abril
Martínez-Ríos, Jacobo
Castañeda-Patlán, M. Cristina
Sarabia-Sánchez, Miguel Angel
Tejeda-Muñoz, Nydia
Chinney-Herrera, Alberto
Soldevila, Gloria
Benelli, Roberto
Santoyo-Ramos, Paula
Poggi, Alessandro
Robles-Flores, Martha
author_sort Saint-Martin, Abril
collection PubMed
description 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.
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spelling pubmed-66276042019-07-23 Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells Saint-Martin, Abril Martínez-Ríos, Jacobo Castañeda-Patlán, M. Cristina Sarabia-Sánchez, Miguel Angel Tejeda-Muñoz, Nydia Chinney-Herrera, Alberto Soldevila, Gloria Benelli, Roberto Santoyo-Ramos, Paula Poggi, Alessandro Robles-Flores, Martha Cancers (Basel) Article 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. MDPI 2019-05-30 /pmc/articles/PMC6627604/ /pubmed/31151160 http://dx.doi.org/10.3390/cancers11060755 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Saint-Martin, Abril
Martínez-Ríos, Jacobo
Castañeda-Patlán, M. Cristina
Sarabia-Sánchez, Miguel Angel
Tejeda-Muñoz, Nydia
Chinney-Herrera, Alberto
Soldevila, Gloria
Benelli, Roberto
Santoyo-Ramos, Paula
Poggi, Alessandro
Robles-Flores, Martha
Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells
title Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells
title_full Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells
title_fullStr Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells
title_full_unstemmed Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells
title_short Functional Interaction of Hypoxia-Inducible Factor 2-Alpha and Autophagy Mediates Drug Resistance in Colon Cancer Cells
title_sort functional interaction of hypoxia-inducible factor 2-alpha and autophagy mediates drug resistance in colon cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627604/
https://www.ncbi.nlm.nih.gov/pubmed/31151160
http://dx.doi.org/10.3390/cancers11060755
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