Heat shock protein 90 (Hsp90) chaperone complex inhibitor, Radicicol, potentiated radiation-induced cell killing in a hormone-sensitive prostate cancer cell line through degradation of the androgen receptor
Heat shock protein 90 (Hsp90) chaperone complex inhibitor, Radicicol, potentiated radiation-induced cell killing in a hormone-sensitive prostate cancer cell line through degradation of the androgen receptor
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DOI：
10.1080/09553000400029460
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发表时间：
2005-01-01
影响因子：
2.6
通讯作者：
Nakano, T
中科院分区：
文献类型：
--
作者：
Harashima, K;Akimoto, T;Nakano, T
到目前为止，关于雄激素或雄激素剥夺如何影响癌细胞对辐射的反应还没有足够的信息。在这项研究中，双氢睾酮（DHT）对细胞增殖活性和放射敏感性的影响进行了研究，在前列腺癌敏感的人前列腺癌细胞系，LNCaP。此外，该研究还研究了热休克蛋白90（Hsp 90）伴侣复合物抑制剂如何改变DHT对细胞放射敏感性的影响，因为雄激素受体（AR）与Hsp 90的结合是维持AR稳定性和功能所必需的。使用对前列腺癌敏感的人前列腺癌细胞系LNCaP。Radicicol被用作已知的Hsp 90分子伴侣复合物抑制剂之一，并在该化合物存在下以500 nM的浓度孵育细胞。通过克隆形成试验测定细胞的放射敏感性;通过Western印迹或免疫荧光法检查蛋白表达的变化。浓度为1 nM的DHT引起细胞增殖活性的增强和放射敏感性的降低。500 nM浓度的根赤霉素消除了DHT诱导的细胞辐射敏感性降低，并协同增强了辐射诱导的细胞杀伤作用。与细胞放射敏感性的变化一致，根赤霉素通过减少AR与Hsp 90的结合来降解AR、Raf-1和HER 2/neu，尽管赫赛汀（一种抗HER 2的单克隆抗体）引起的HER 2/neu的选择性降解不影响细胞的放射敏感性。结果表明，热休克蛋白90分子伴侣复合物可能是一个潜在的分子靶点增强辐射诱导的细胞杀伤的前列腺癌细胞株。
Until now, there has not been enough information on how androgens or androgen deprivation may influence the response of cancer cells to radiation. In this study, the effect of dihydrotestosterone (DHT) on cellular proliferative activity and radiosensitivity was examined in a hormone-sensitive human prostate cancer cell line, LNCaP. In addition, the study also examined how a heat shock protein 90 (Hsp90) chaperone complex inhibitor modified the effect of DHT on the radiosensitivity of the cells, because binding of the androgen receptor (AR) to Hsp90 is required to maintain the stability and functioning of AR. The hormone-sensitive human prostate cancer cell line, LNCaP, was used. Radicicol was used as one of the known Hsp90 chaperone complex inhibitors, and the cells were incubated in the presence of this compound at a concentration of 500 nM. Cellular radiosensitivity was determined by the clonogenic assay; the changes in the protein expression were examined by Western blotting or immunofluorescence. DHT at a concentration of 1 nM caused enhancement of the proliferative activity and reduction of the radiosensitivity of the cells. Radicicol at a concentration of 500 nM abolished the DHT-induced decrease in cellular radiosensitivity and potentiated the radiation-induced cell killing synergistically. Consistent with the changes in the cellular radiosensitivity, radicicol degraded AR, Raf-1 and HER2/neu via reduced binding of AR to Hsp90, although selective degradation of HER2/neu caused by Herceptin, a monoclonal antibody against HER2, did not affect the cellular radiosensitivity. The results suggest that the Hsp90 chaperone complex may be a potential molecular target for potentiation of radiation-induced cell killing in a hormone-sensitive prostate cancer cell line.