Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone
Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone
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DOI：
10.1073/pnas.0805354105
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发表时间：
2008-10-07
影响因子：
11.1
通讯作者：
Neckers, Len
中科院分区：
文献类型：
--
作者：
Yano, Akihiro;Tsutsumi, Shinji;Neckers, Len
Hsp 90抑制剂正在晚期癌症患者中进行广泛评估。然而，Hsp 90抑制对正常组织中信号通路的影响以及这可能对这些分子靶向药物的抗肿瘤活性的影响尚未得到严格的检查。乳腺癌和前列腺癌是在动物异种移植模型和患者的早期研究中对Hsp 90抑制剂有反应的癌症之一。由于这些癌症经常转移到骨，因此确定Hsp 90抑制剂在骨环境中的影响非常重要。在目前的研究中，我们表明，与其体外抗前列腺癌细胞的活性和其对s.c.在前列腺癌异种移植物中，Hsp 90抑制剂17-AAG刺激PC-3 M前列腺癌细胞的骨内生长。这种活性不是通过对肿瘤的直接作用介导的，而是通过Hsp 90依赖性刺激破骨细胞成熟介导的。热休克蛋白90抑制瞬时激活破骨细胞Src激酶和促进Src依赖性Akt激活。这两种激酶都是破骨细胞成熟的关键驱动因素，三种阻断破骨细胞生成的药物，Src抑制剂达沙替尼，双膦酸盐阿仑膦酸盐和破骨细胞特异性骨诱导剂逆转录酶A，显着降低了17-AAG刺激的骨肿瘤生长。这些数据强调了理解Hsp 90在调节正常组织以及癌细胞中的信号转导通路中所起的复杂作用的重要性，并且它们表明局部肿瘤环境的药物依赖性调节可能深刻地影响Hsp 90定向治疗的抗肿瘤功效。
Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate carcinomas are among those cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against prostate cancer cells in vitro and its inhibition of s.c. prostate cancer xenografts, the Hsp90 inhibitor 17-AAG stimulates the intraosseous growth of PC-3M prostate carcinoma cells. This activity is mediated not by a direct effect on the tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast Src kinase and promotes Src-dependent Akt activation. Both kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor dasatinib, the bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer reveromycin A, markedly reduced 17-AAG-stimulated tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in cancer cells, and they demonstrate that drug-dependent modulation of the local tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed therapy.