Department of Hematology and Oncology, Medical Center of the Georg-August-University Göttingen, Göttingen, Germany.
Cell Commun Signal. 2009 Jul 16;7:17. doi: 10.1186/1478-811X-7-17.
In classical Hodgkin lymphoma (cHL) chemotherapeutic regimens are associated with stagnant rates of secondary malignancies requiring the development of new therapeutic strategies. We and others have shown that permanently activated Signal Transducer and Activator of Transcription (STAT) molecules are essential for cHL cells. Recently an overexpression of heat-shock protein 90 (HSP90) in cHL cells has been shown and inhibition of HSP90 seems to affect cHL cell survival. Here we analysed the effects of HSP90 inhibition by geldanamycin derivative 17-AAG or RNA interference (RNAi) on aberrant Jak-STAT signaling in cHL cells. Treatment of cHL cell lines with 17-AAG led to reduced cell proliferation and a complete inhibition of STAT1, -3, -5 and -6 tyrosine phosphorylation probably as a result of reduced protein expression of Janus kinases (Jaks). RNAi-mediated inhibition of HSP90 showed similar effects on Jak-STAT signaling in L428 cHL cells. These results suggest a central role of HSP90 in permanently activated Jak-STAT signaling in cHL cells. Therapeutics targeting HSP90 may be a promising strategy in cHL and other cancer entities associated with deregulated Jak-STAT pathway activation.
在经典霍奇金淋巴瘤（cHL）中，化疗方案与继发性恶性肿瘤的停滞率相关，这需要开发新的治疗策略。我们和其他人已经表明，信号转导和转录激活因子（STAT）分子的永久激活对于 cHL 细胞是必不可少的。最近已经表明，cHL 细胞中热休克蛋白 90（HSP90）的过度表达，并且抑制 HSP90 似乎会影响 cHL 细胞的存活。在这里，我们分析了geldanamycin 衍生物 17-AAG 或 RNA 干扰（RNAi）对 cHL 细胞中异常 Jak-STAT 信号的抑制作用。用 17-AAG 处理 cHL 细胞系导致细胞增殖减少和 STAT1、-3、-5 和 -6 酪氨酸磷酸化的完全抑制，可能是由于 Janus 激酶（Jaks）的蛋白表达减少所致。HSP90 的 RNAi 介导抑制在 L428 cHL 细胞中的 Jak-STAT 信号中显示出相似的作用。这些结果表明 HSP90 在 cHL 细胞中永久激活的 Jak-STAT 信号中起核心作用。针对 HSP90 的治疗可能是 cHL 和其他与 Jak-STAT 途径激活失调相关的癌症实体的有前途的策略。
