Tumor necrosis factor-α blocks apoptosis in melanoma cells when BRAF signaling is inhibited
Tumor necrosis factor-α blocks apoptosis in melanoma cells when BRAF signaling is inhibited
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DOI：
10.1158/0008-5472.can-06-1880
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发表时间：
2007-01-01
期刊：
影响因子：
11.2
通讯作者：
Marais, Richard
中科院分区：
文献类型：
--
作者：
Gray-Schopfer, Vanessa C.;Karasarides, Maria;Marais, Richard
蛋白激酶BRAF是RAS/RAF/促分裂原活化蛋白激酶/细胞外信号调节激酶（ERK）激酶（MEK）/ERK信号传导途径的组分，响应于细胞外信号调节细胞命运。BRAF中的激活突变发生在类似于70%的人类黑色素瘤中。活性蛋白质刺激组成性途径信号传导、增殖和存活。因此，抑制黑色素瘤细胞中的BRAF信号传导导致细胞周期停滞并通过细胞凋亡诱导细胞死亡，从而验证BRAF作为重要的治疗靶标。在这里，我们表明，在黑色素瘤细胞中的BRAF信号抑制诱导的细胞凋亡可以防止，如果细胞与肿瘤坏死因子（TNF）-α治疗。这允许细胞从BRAF信号传导的抑制中恢复并重新进入细胞周期。这种效应是由于特异性TNF-α和BRAF相互作用而发生的，因为TNF-α在顺铂、氮芥或毒胡萝卜素存在下不能阻止细胞死亡。此外，细胞因子Fas配体、TNF相关凋亡诱导配体、白细胞介素（IL）-1和IL-6在BRAF信号传导被抑制时不能阻止细胞死亡。存活机制需要核因子-κ B（NF-κ B）转录因子活性，其在这些细胞中被TNF-α强烈诱导。这些发现表明，靶向BRAF/MEK通路的药物可以与靶向TNF-α和/或NF-κ B信号传导的药物组合，为治疗黑色素瘤提供令人兴奋的新治疗机会。
The protein kinase BRAF, a component of the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway, regulates cell fate in response to extracellular signals. Activating mutations in BRAF occur in similar to 70% of human melanomas. The active proteins stimulate constitutive pathway signaling, proliferation, and survival. Thus, inhibition of BRAF signaling in melanoma cells causes cell cycle arrest and induces cell death through apoptosis, validating BRAF as an important therapeutic target. Here, we show that the apoptosis induced by inhibition of BRAF signaling in melanoma cells can be prevented if the cells are treated with tumor necrosis factor (TNF)-alpha. This allows the cells to recover from the inhibition of BRAF signaling and reenter the cell cycle. This effect occurs due to a specific TNF-alpha and BRAF interaction because TNF-alpha does not prevent cell death in the presence of cisplatin, nitrogen mustard or thapsigargin. Furthermore, the cytokines Fas ligand, TNF-related apoptosis-inducing ligand, interleukin (IL)-1, and IL-6 do not prevent cell death when BRAF signaling is inhibited. The survival mechanism requires nuclear factor-kappa B (NF-kappa B) transcription factor activity, which is strongly induced by TNF-alpha in these cells. These findings suggest that drugs that target the BRAF/MEK pathway could be combined with agents that target TNF-alpha and/or NF-kappa B signaling to provide exciting new therapeutic opportunities for the treatment of melanoma.