Targeting Heat Shock Protein 90 Overrides the Resistance of Lung Cancer Cells by Blocking Radiation-Induced Stabilization of Hypoxia-Inducible Factor-1 alpha
- Authors
- Kim, Woo-Young; Oh, Seung Hyun; Woo, Jong-Kyu; Hong, Waun Ki; Lee, Ho-Young
- Issue Date
- Feb-2009
- Publisher
- AMER ASSOC CANCER RESEARCH
- Citation
- CANCER RESEARCH, v.69, no.4, pp 1624 - 1632
- Pages
- 9
- Journal Title
- CANCER RESEARCH
- Volume
- 69
- Number
- 4
- Start Page
- 1624
- End Page
- 1632
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/148106
- DOI
- 10.1158/0008-5472.CAN-08-0505
- ISSN
- 0008-5472
- Abstract
- Hypoxia-inducible factor-1 (HIF-1) has been suggested to play a major role in tumor radioresistance. However, the mechanisms through which irradiation regulates HIF-1 alpha expression remain unclear. The purpose of this study was to investigate the mechanisms that mediate HIF-1 activation and thus radioresistance. Here, we show that irradiation induces survival and angiogenic activity in a subset of radioresistant lung cancer cell lines by elevating HIF-1 alpha protein expression. Radiation induced HIF-1 alpha protein expression mainly through two distinct pathways, including an increase in de novo protein synthesis via activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and stabilization of HIF-1 alpha protein via augmenting the interaction between heat shock protein 90 (Hsp90) and HIF-1 alpha protein. Whereas the PI3K/Akt/mTOR pathway was activated by irradiation in all the lung cancer cells examined, the Hsp90-HIF-1 alpha interaction was enhanced in the resistant cells only. Inhibition of Hsp90 function by 17-allylamino-17-demethoxygeldanamycin or deguelin, a novel natural inhibitor of Hsp90, suppressed increases in HIF-1 alpha/Hsp90 interaction and HIF-1 alpha expression in radioresistant cells. Furthermore, combined treatment of radiation with deguelin significantly d
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