Functional interaction of hypoxia-inducible factor 2-alpha and autophagy mediates drug resistance in colon cancer cells

Martha Robles-Flores, Abril Saint-Martin, Jacobo Martínez-Ríos, M. Cristina Castañeda-Patlán, Miguel Angel Sarabia-Sánchez, Nydia Tejeda-Muñoz, Alberto Chinney-Herrera, Gloria Soldevila, Roberto Benelli, Paula Santoyo-Ramos, Alessandro Poggi

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number755
Issue number6
Publication statusPublished - Jun 1 2019


  • Autophagy
  • Colon cancer
  • Drug resistance
  • Hypoxia-inducible factors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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