Multifaceted intervention by the Hsp90 inhibitor ganetespib (STA-9090) in cancer cells with activated JAK/STAT signaling.
Multifaceted intervention by the Hsp90 inhibitor ganetespib (STA-9090) in cancer cells with activated JAK/STAT signaling.
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DOI：
10.1371/journal.pone.0018552
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发表时间：
2011-04-14
期刊：
影响因子：
3.7
通讯作者：
Blackman RK
中科院分区：
文献类型：
--
作者：
Proia DA;Foley KP;Korbut T;Sang J;Smith D;Bates RC;Liu Y;Rosenberg AF;Zhou D;Koya K;Barsoum J;Blackman RK
越来越多的证据表明，JAK信号失控发生在多种癌症类型中。特别是，JAK2的突变可以导致STAT转录因子的结构性激活，并导致致癌生长。JAK激酶是已建立的Hsp90客户蛋白，在这里，我们证明了新型小分子Hsp90抑制剂ganetespib(以前的STA-9090)在一系列依赖JAK2活性生长和生存的实体和血液肿瘤细胞中显示出强大的体外和体内活性。值得注意的是，Ganetespib治疗导致JAK2的持续耗尽，包括成分上具有活性的JAK2V617F突变体，随后STAT活性丧失，STAT靶基因表达减少。相比之下，PAN-JAK抑制剂P6的治疗只会对这些过程产生短暂的影响。进一步区分这些干预模式，RNA和蛋白质表达研究表明，ganetespib额外调节细胞周期调节蛋白，而P6不调节。Ganetespib对细胞生长和细胞分裂信号的伴随影响在异种移植模型和播散性JAK/STAT驱动的白血病小鼠模型中转化为强大的抗肿瘤效果。总体而言，我们的发现支持Hsp90抑制作为一种新的治疗方法来对抗依赖JAK/STAT信号的疾病，而ganetespib的多模式作用显示出比JAK特异性抑制剂的优势。
There is accumulating evidence that dysregulated JAK signaling occurs in a wide variety of cancer types. In particular, mutations in JAK2 can result in the constitutive activation of STAT transcription factors and lead to oncogenic growth. JAK kinases are established Hsp90 client proteins and here we show that the novel small molecule Hsp90 inhibitor ganetespib (formerly STA-9090) exhibits potent in vitro and in vivo activity in a range of solid and hematological tumor cells that are dependent on JAK2 activity for growth and survival. Of note, ganetespib treatment results in sustained depletion of JAK2, including the constitutively active JAK2V617F mutant, with subsequent loss of STAT activity and reduced STAT-target gene expression. In contrast, treatment with the pan-JAK inhibitor P6 results in only transient effects on these processes. Further differentiating these modes of intervention, RNA and protein expression studies show that ganetespib additionally modulates cell cycle regulatory proteins, while P6 does not. The concomitant impact of ganetespib on both cell growth and cell division signaling translates to potent antitumor efficacy in mouse models of xenografts and disseminated JAK/STAT-driven leukemia. Overall, our findings support Hsp90 inhibition as a novel therapeutic approach for combating diseases dependent on JAK/STAT signaling, with the multimodal action of ganetespib demonstrating advantages over JAK-specific inhibitors.
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影响因子：
6.5
作者：
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Rowntree, Clare
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