| First Author | Zhang M | Year | 2015 |
| Journal | Radiat Res | Volume | 183 |
| Issue | 6 | Pages | 594-609 |
| PubMed ID | 25973951 | Mgi Jnum | J:316996 |
| Mgi Id | MGI:6843863 | Doi | 10.1667/RR14016.1 |
| Citation | Zhang M, et al. (2015) HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism. Radiat Res 183(6):594-609 |
| abstractText | Hypoxia is a major cause of radiation resistance, which may predispose to local recurrence after radiation therapy. While hypoxia increases tumor cell survival after radiation exposure because there is less oxygen to oxidize damaged DNA, it remains unclear whether signaling pathways triggered by hypoxia contribute to radiation resistance. For example, intratumoral hypoxia can increase hypoxia inducible factor 1 alpha (HIF-1alpha), which may regulate pathways that contribute to radiation sensitization or radiation resistance. To clarify the role of HIF-1alpha in regulating tumor response to radiation, we generated a novel genetically engineered mouse model of soft tissue sarcoma with an intact or deleted HIF-1alpha. Deletion of HIF-1alpha sensitized primary sarcomas to radiation exposure in vivo. Moreover, cell lines derived from primary sarcomas lacking HIF-1alpha, or in which HIF-1alpha was knocked down, had decreased clonogenic survival in vitro, demonstrating that HIF-1alpha can promote radiation resistance in a cell autonomous manner. In HIF-1alpha-intact and -deleted sarcoma cells, radiation-induced reactive oxygen species, DNA damage repair and activation of autophagy were similar. However, sarcoma cells lacking HIF-1alpha had impaired mitochondrial biogenesis and metabolic response after irradiation, which might contribute to radiation resistance. These results show that HIF-1alpha promotes radiation resistance in a cell autonomous manner. |
