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-1alpha 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-1alpha protein expression. Radiation induced HIF-1alpha 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-1alpha protein via augmenting the interaction between heat shock protein 90 (Hsp90) and HIF-1alpha protein. Whereas the PI3K/Akt/mTOR pathway was activated by irradiation in all the lung cancer cells examined, the Hsp90-HIF-1alpha 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-1alpha/Hsp90 interaction and HIF-1alpha expression in radioresistant cells. Furthermore, combined treatment of radiation with deguelin significantly decreased the survival and angiogenic potential of radioresistant lung cancer cells in vitro. We finally determined in vivo that systemic administration of deguelin resulted in profound inhibition of tumor growth and angiogenesis when combined with radiation. These results provide a strong rationale to target Hsp90 as a means to block radiation-induced HIF-1alpha and thus to circumvent radioresistance in lung cancer cells.
Highlights
Researchers have made extensive efforts to understand the mechanisms underlying radioresistance and to discover novel molecular targets whose modulation could enhance radiotherapeutic response [1]
We investigated whether the response of lung cancer cells to radiation was associated with their angiogenic activity by testing the effects of the conditioned medium (CM) from the irradiated non–small cell lung cancer cell (NSCLC) cells on human umbilical vein endothelial cells (HUVEC) viability
Because irradiation did not change the total level of heat shock protein 90 (Hsp90) protein in H1299 cells, we examined the effects of irradiation on the interaction between HIF-1a and Hsp90 by coimmunoprecipitation assays
Summary
Researchers have made extensive efforts to understand the mechanisms underlying radioresistance and to discover novel molecular targets whose modulation could enhance radiotherapeutic response [1]. Radiation increases hypoxia-inducible factor-1 (HIF-1) activity, which has been suggested to be dominant governor of tumor response to irradiation through multiple mechanisms [2], causing radioprotection of the tumor vasculature [3,4,5]. Blockade of HIF-1 significantly increased tumor radiosensitivity by enhanc-. Overexpression of HIF-1a in tumor biopsy samples has been associated with a poor response to radiotherapy in multiple cancer types [6]. Cancer cells without functional HIF-1a [7, 8] and tumor xenografts of HIF-1a– null cells are more radiosensitive than their HIF-1a–expressing counterparts [7]
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