Inhibition of Hsp90 Leads to Cell Cycle Arrest and Apoptosis in Human Malignant Pleural Mesothelioma
Inhibition of Hsp90 Leads to Cell Cycle Arrest and Apoptosis in Human Malignant Pleural Mesothelioma
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DOI：
10.1097/jto.0b013e3181839693
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发表时间：
2008-10-01
影响因子：
20.4
通讯作者：
Jablons, David M.
中科院分区：
文献类型：
--
作者：
Okamoto, Junichi;Mikami, Iwao;Jablons, David M.
简介：热休克蛋白 90 (Hsp90) 是一种丰富的分子伴侣，可介导与促进细胞生长和存活相关的多种蛋白质的成熟和稳定性。 Hsp90 功能的抑制会导致其错误折叠的客户蛋白被蛋白酶体降解。最近，Hsp90 被发现对癌细胞的生长和存活至关重要，其抑制剂已用于 I 期和 II 期临床试验。方法：我们研究了 Hsp90 的小分子抑制剂 17-烯丙基氨基-17-去甲氧基格尔德霉素 (17-AAG) 如何与人类恶性胸膜间皮瘤 (MM) 相关。结果：我们发现 17-AAG 导致显着的 G1在所有检测的人恶性胸膜间皮瘤细胞系中，G2/M 细胞周期停滞、细胞增殖抑制以及 AKT、AKT1 和生存素表达降低。我们还在用 17-AAG 处理的所有 MM 细胞系中观察到显着的细胞凋亡诱导。此外，17-AAG 诱导新鲜培养的原代 MM 细胞凋亡，并引起与 17-AAG 处理的 MM 细胞系相同的信号变化。结论：这些结果表明 Hsp90 与 MM 的生长和存活密切相关，抑制 Hsp90 可能在治疗 MM 中具有治疗潜力。
Introduction: Heat shock protein 90 (Hsp90) is an abundant molecular chaperone that mediates the maturation and stability of a variety of proteins associated with the promotion of cell growth and survival. Inhibition of Hsp90 function leads to proteasomal degradation of its mis-folded client proteins. Recently, Hsp90 has emerged as being of prime importance to the growth and survival of cancer cells and its inhibitors have already been used in phase I and II clinical trials.Methods: We investigated how 17-allylamino-17-demethoxygeldanamycin (17-AAG), a small molecule inhibitor of Hsp90, is implicated in human malignant pleural mesothelionta (MM).Results: We found that 17-AAG led to significant G1 or G2/M cell cycle arrest, inhibition of cell proliferation, and decrease of AKT, AKT1, and survivin expression in all human malignant pleural mesothelioma cell lines examined. We also observed significant apoptosis induction in all MM cell lines treated with 17-AAG. Furthermore, 17-AAG induced apoptosis in freshly cultured primary MM cells and caused signaling changes identical to those in 17-AAG treated MM cell lines.Conclusion: These results suggest that Hsp90 is strongly associated with the growth and survival of MM and that inhibition of Hsp90 may have therapeutic potential in the treatment of MM.