Abstract
Hypoxia is a hallmark of solid tumors, which presents a major obstacle to the effectiveness of radiation therapy. However, the function and the importance of molecular response have not been well defined. In the present study, hypoxia-induced autophagy and its effect on the response of breast cancer cells to ionizing radiation were examined. Results showed that hypoxic exposure induced a marked accumulation of autophagosomes accompanied by mRNA induction of the autophagy-related genes Beclin-1, Atg5, Atg7, and Atg12. The elevated autophagic activity was associated with increased radioresistance of tumor cells. Accordingly, blockade of autophagy by pharmacological inhibition or Beclin-1 small interfering RNA (siRNA) contributed to retardation of DNA double-strand breaks (DSB) repair and significant radiosensitization. Our data indicate that strategies designed to suppress autophagic activity may represent promising new therapies for sensitizing hypoxic breast cancer cells to ionizing radiation (IR).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis Regulatory Proteins / metabolism
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Autophagy / genetics
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Autophagy / radiation effects*
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Autophagy-Related Protein 12
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Autophagy-Related Protein 5
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Autophagy-Related Protein 7
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Beclin-1
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Breast Neoplasms / radiotherapy*
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Cell Hypoxia
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Female
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Gene Expression Regulation, Neoplastic / radiation effects
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Humans
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MCF-7 Cells
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Membrane Proteins / metabolism
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Microtubule-Associated Proteins / metabolism
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RNA, Messenger / genetics
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Radiation, Ionizing
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Small Ubiquitin-Related Modifier Proteins / metabolism
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Ubiquitin-Activating Enzymes / metabolism
Substances
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ATG12 protein, human
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ATG5 protein, human
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Apoptosis Regulatory Proteins
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Autophagy-Related Protein 12
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Autophagy-Related Protein 5
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BECN1 protein, human
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Beclin-1
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Membrane Proteins
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Microtubule-Associated Proteins
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RNA, Messenger
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Small Ubiquitin-Related Modifier Proteins
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ATG7 protein, human
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Autophagy-Related Protein 7
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Ubiquitin-Activating Enzymes