Targeting heat shock protein 90 overrides the resistance of lung cancer cells by blocking radiation-induced stabilization of hypoxia-inducible factor-1alpha.
Targeting heat shock protein 90 overrides the resistance of lung cancer cells by blocking radiation-induced stabilization of hypoxia-inducible factor-1alpha.
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DOI：
10.1158/0008-5472.can-08-0505
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发表时间：
2009-02-15
期刊：
影响因子：
11.2
通讯作者：
Lee HY
中科院分区：
文献类型：
--
作者：
Kim WY;Oh SH;Woo JK;Hong WK;Lee HY
缺氧诱导因子-1（HIF-1）在肿瘤放射抵抗中起重要作用。然而，辐射调节HIF-1α表达的机制仍不清楚。本研究的目的是探讨介导HIF-1激活和辐射抗性的机制。在这里，我们发现，辐射诱导生存和血管生成活性的放射抵抗肺癌细胞系的一个子集，通过提高HIF-1α蛋白表达。辐射诱导HIF-1α蛋白表达主要通过两条不同的途径，一条是激活PI 3 K/Akt/mTOR促进HIF-1α蛋白的从头合成，另一条是增强热休克蛋白90（Hsp 90）与HIF-1α蛋白的相互作用稳定HIF-1 α蛋白。尽管PI 3 K/Akt/mTOR通路在所有检测的肺癌细胞中被辐射激活，但HSP 90-HIF-1α相互作用仅在抗性细胞中增强。用17-AAG或一种新的HSP 90天然抑制剂鱼藤素抑制HSP 90的功能，可抑制辐射抗性细胞中HIF-1α/Hsp 90相互作用和HIF-1α表达的增加。此外，联合治疗辐射与鱼藤素显着降低存活率和血管生成的潜力，辐射耐药肺癌细胞在体外。我们最终在体内确定，当与辐射组合时，鱼藤素的全身施用导致对肿瘤生长和血管生成的深刻抑制。这些结果为靶向Hsp 90作为阻断辐射诱导的HIF-1α从而规避肺癌细胞中的辐射抗性的手段提供了强有力的理论基础。
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-1α 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-1α protein expression. Radiation induced HIF-1α protein expression mainly through two distinct pathways, including an increase in de novo protein synthesis via activation of PI3K/Akt/mTOR and stabilization of HIF-1α protein via augmenting the interaction between heat shock protein 90 (Hsp90) and HIF-1α protein. While the PI3K/Akt/mTOR pathway was activated by irradiation in all the lung cancer cells examined, the HSP90-HIF-1α interaction was enhanced in the resistant cells only. Inhibition of Hsp90 function by 17-AAG or deguelin, a novel natural inhibitor of HSP90, suppressed increases in HIF-1α/Hsp90 interaction and HIF-1α 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-1α and thus to circumvent radioresistance in lung cancer cells.