The role of hypoxia-inducible factor-1α in radiation-induced autophagic cell death in breast cancer cells

Tumour Biol. 2015 Sep;36(9):7077-83. doi: 10.1007/s13277-015-3425-z. Epub 2015 Apr 15.


Hypoxia-inducible factor-1α (HIF-1α) is a major effector in cell survival response to hypoxia, while the roles of HIF-1α in radiation-induced autophagy are still unclear in breast cancer cells. Human breast cancer carcinoma MCF-7 cells were stably transfected with pSUPER-shRNA against human HIF-1α or a scrambled sequence with no homology to mammalian genes, named as pSUPER-HIF-1α and pSUPER-SC, respectively. Cell Counting Kit-8 (CCK-8) assay and colony formation assay were used to detect cell viability, Western blot was used to detect protein expression, monodansylcadaverine (MDC) staining was used to analyze autophagy, and Hoechts/PI staining was used to assess apoptosis. Ionizing radiation (IR) and cobalt chloride (CoCl2) could induce HIF-1α expression and increase the microtubule-associated protein 1 light chain 3 (MAPLC3)-II/MAPLC3-I ratio, especially in radiation + CoCl2 group. After the silencing of HIF-1α, the radiosensitivity of MCF-7 cells increased and the autophagy level decreased in response to DNA damage induced by ionizing radiation, but there was no influence on IR-induced apoptosis. HIF-1α silencing also increased the expression of phospho-Akt, mTOR, and P70S6K and activated the mTOR signals significantly. Hypoxia can induce autophagy and also improve the IR-induced autophagy via the suppression of Akt/mTOR/P70S6K pathway, which consequently lead to radioresistance.

Keywords: Apoptosis; Autophagy; Breast cancer; HIF-1α; Radiosensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Autophagy / genetics*
  • Autophagy / radiation effects
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Hypoxia / genetics
  • Cell Hypoxia / radiation effects
  • Cell Survival / radiation effects
  • DNA Damage / radiation effects
  • Female
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • MCF-7 Cells
  • Mice
  • Neoplasms, Radiation-Induced / genetics*
  • Neoplasms, Radiation-Induced / pathology
  • RNA, Small Interfering / genetics
  • Radiation Tolerance / genetics
  • Radiation, Ionizing


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering