Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor
Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor
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DOI：
10.1038/onc.2013.45
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发表时间：
2014-02-27
期刊：
影响因子：
8
通讯作者：
Rizos, H.
中科院分区：
文献类型：
--
作者：
Becker, T. M.;Boyd, S. C.;Rizos, H.
大约50%的黑色素瘤依赖于突变B-RAF的增殖、转移和存活。用高度靶向的化合物抑制致癌的B-RAF在B-RAF突变型黑色素瘤患者中产生了显著但短暂的临床反应。B-RAF下游信号转导的再激活通常与对B-RAF抑制剂的获得性耐药性相关，B-RAF靶点的鉴定可能为管理黑色素瘤提供新的策略。已知致癌B-RAF（V600 E）促进抗凋亡蛋白Mcl-1的稳定磷酸化，其与黑色素瘤存活和化学抗性有关。我们现在表明，B-RAFV 600 E信号也诱导黑素细胞和黑色素瘤中Mcl-1的转录。我们证明，STAT 3丝氨酸-727和酪氨酸-705磷酸化的激活是由B-RAF（V600 E）的活性，并Mcl-1启动子是依赖于STAT共识网站B-RAF介导的激活。因此，STAT 3活性的抑制破坏了B-RAF（V600 E）介导的Mcl-1诱导并降低了黑素瘤细胞存活。我们认为STAT 3在B-RAF（V600 E）黑色素瘤的生存和化疗耐药性中起着重要作用。
Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAF(V600E) is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAFV600E signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of STAT3 serine-727 and tyrosine-705 phosphorylations is promoted by B-RAF(V600E) activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation. Consequently, suppression of STAT3 activity disrupted B-RAF(V600E)-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that STAT3 has a central role in the survival and contributes to chemoresistance of B-RAF(V600E) melanoma.