Radiosensitization by inhibition of Hsp90 and microenvironmental factors

通过抑制 Hsp90 和微环境因素实现放射增敏

基本信息

批准号：
14370283
负责人：
KUBOTA Nobuo
金额：
$ 6.98万
依托单位：
Ibaraki Prefectural University of Health Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370283/
关键词：
Hsp90 GA 17AAG Radiosensitization PI3K-Akt Apoptosis Spheroid Hsp90 geldanamycin PI3K Akt スフェロイド

项目摘要

Activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway is known to induce tumor radioresistance. In the current studies, we examined the ability of 17-Allylamino-17-demethoxygeldanamycin (17AAG), which decreases the levels of Hsp90 client proteins including components of the PI3K-Akt pathway, to sensitize radioresistant human squamous cell carcinoma cells to X-irradiation. 17AAG (0.2 μM) enhanced the radiosensitivity more effectively in radioresistant SQ20B and SCC 13 cells than in radiosensitive SCC61 cells. However, in all three cell lines, 17AAG increased radiation-induced apoptosis by reducing the expression of the epidermal growth factor receptor and ErbB-2 and inhibiting the phosphorylation of Akt. Furthermore, 17AAG (1 μM) sensitized SQ20B spheroids to radiation, and inhibition of Akt activation by 17AAG increased radiation-induced apoptosis in spheroids. The findings suggest that 17AAG effectively sensitizes radioresistant cells to radiation by inhibiting the PI3K-Akt pathway.We also tested the effect of a combination of GA and radiation on cell survival, PI3K/Akt-related proteins and apoptosis induction in human tumor and normal cells. GA sensitized tumour cells in preference to normal cells to radiation. In addition, a combination of radiation and GA abolished Akt activities and strongly enhanced the induction of apoptosis in tumour cells which depend on Akt protein activities for cell survival. The present data support the hypothesis that GA sensitizes tumour cells by modulating the balance among mitogenic, antiproliferative and apoptotic pathways. Thus, targeting Hsp90 in tumour cells may lead to the development of new radiosensitizing strategies in radiotherapy.

已知磷脂酰肌醇3-激酶（PI3K）-AKT途径的激活已知会诱导肿瘤放射线。在目前的研究中，我们研究了17-乙酰氨基-17-甲氧基甲霉素（17AAG）的能力，该霉素（17AAG）降低了HSP90客户蛋白的水平，包括PI3K-AKT途径的成分，对敏感的放射性放射性放射性辐射的人类鳞状细胞癌细胞至X-膜片。 17AAG（0.2μM）比放射性SQ20B和SCC 13细胞在放射性SCC61细胞中更有效地增强了放射敏性。但是，在所有三种细胞系中，17AAG通过降低表皮生长因子受体和ERBB-2的表达并抑制Akt的磷酸化来增加辐射诱导的凋亡。此外，17AAG（1μM）敏感的SQ20B球形素对辐射，并通过17AAG抑制Akt激活，增加了辐射诱导的球体凋亡。研究结果表明，17AAG通过抑制PI3K-AKT途径有效地感觉到放射性细胞对辐射，我们还测试了GA和辐射对人类肿瘤和正常细胞中与细胞存活，PI3K/AKT相关蛋白质和凋亡的影响的影响。 GA敏感的肿瘤细胞优先于正常细胞而不是辐射。此外，辐射和GA的结合消除了AKT活性，并强烈增强了肿瘤细胞中凋亡的诱导，这依赖于Akt蛋白活性用于细胞存活。目前的数据支持以下假设：GA通过调节有丝分裂，抗增殖和凋亡途径之间的平衡来感知肿瘤细胞。这是针对肿瘤细胞中HSP90的靶向可能导致放射疗法中新的放射敏化策略的发展。