Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context.
Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context.
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DOI：
10.1016/j.yexcr.2007.06.022
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发表时间：
2007-11
影响因子：
3.7
通讯作者：
M. Theodoraki;M. Kunjappu;D. Sternberg;A. Caplan
中科院分区：
文献类型：
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作者：
M. Theodoraki;M. Kunjappu;D. Sternberg;A. Caplan
Hsp90 抑制剂目前正处于癌症治疗的临床试验中，因为它们能够促进致癌蛋白激酶和核受体的蛋白酶体降解。最近的研究结果表明，癌细胞比健康组织的细胞对这些抑制剂更敏感。我们分析了永生化细胞系 Ba/F3 在逆转录病毒载体表达的致癌酪氨酸融合激酶 NPM-ALK 存在和不存在的情况下对 Hsp90 抑制剂格尔德霉素的敏感性。我们的结果表明，NPM-ALK 表达使 Akt 和 Cdk4 在格尔德霉素存在下更能抵抗降解，并且细胞凋亡量略有减少。通过比较翻译抑制和格尔德霉素处理后激酶的更新，探讨了 NPM-ALK 对 Akt 稳定性影响的机制。我们观察到，在存在 GA 的情况下，Akt 的降解速度比在没有 NPM-ALK 表达的情况下抑制翻译时更快。这表明 NPM-ALK 可以保护成熟激酶。此外，Akt 未能与表达 NPM-ALK 的细胞中的 Cdc37 伴侣结合，这也与 Akt 稳定性增加相关。
Hsp90 inhibitors are currently in clinical trials for cancer therapy based on their ability to promote proteasomal degradation of oncogenic protein kinases and nuclear receptors. Results from recent studies suggest that cancer cells are more sensitive to these inhibitors than cells from healthy tissues. We analyzed an immortalized cell line Ba/F3 for sensitivity to the Hsp90 inhibitor geldanamycin in the absence and presence of the oncogenic tyrosine fusion kinase NPM-ALK expressed from a retroviral vector. Our results showed that NPM-ALK expression makes Akt and Cdk4 more resistant to degradation in the presence of geldanamycin, and there was a slightly reduced amount of apoptosis. The mechanism underlying the effect of NPM-ALK on Akt stability was probed by comparison of the turnover of the kinase after translation inhibition and geldanamycin treatment. We observed that Akt was degraded more rapidly in the presence of GA than upon translation inhibition without NPM-ALK expression. This suggests that NPM-ALK protects the mature kinase. Furthermore, Akt failed to bind to the Cdc37 chaperone in cells expressing NPM-ALK, which also correlates with increased Akt stability.