The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells (Retracted article. See vol. 79, pg. 5459, 2019)
The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells (Retracted article. See vol. 79, pg. 5459, 2019)
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DOI：
10.1158/0008-5472.can-05-0808
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发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Mier, JW
中科院分区：
文献类型：
--
作者：
Panka, DJ;Wang, W;Mier, JW
丝裂原激活蛋白激酶（MAPK）在大多数黑色素瘤中被激活，其活性对于细胞生存至关重要。在本报告中，我们研究了新型 raf 抑制剂 BAY 43-9006 对黑色素瘤细胞活力和细胞内信号传导的影响，发现它通过不依赖 caspase 的机制诱导细胞凋亡。在抑制细胞外信号调节激酶 (ERK) 磷酸化的浓度下，BAY 43-9006 使 Ser(75) 和 Ser(99) 上的 Bad 去磷酸化，激活 Bak 和 Bax，并降低线粒体跨膜电位。 BAY 43-9006 (sor-afenib) 在 A2058 和 SKMEL5 黑色素瘤细胞中以不依赖 MAPK 的方式下调 Bcl-2 和 Bcl-X-L 的水平，但在耐药性更强的 A375 细胞中则不然。在测试的三个细胞系中，只有 A375 细胞通过敲除 Bad 而被从 BAY 43-9006 诱导的细胞凋亡中拯救出来。 BAY 43-9006 诱导聚 (ADP-核糖) 聚合酶裂解以及细胞色素 c 和 SMAC 的线粒体释放。然而，泛 caspase 抑制剂 Z-VAD-fmk 对药物仅具有适度的保护作用，表明 BAY 439006 诱导的细胞凋亡很大程度上不依赖于 caspase。 BAY 43-9006 但不是 MAP/ERK 激酶抑制剂 PD98059 或 U0126 诱导 A2058 和 SKMEL5 细胞中凋亡诱导因子 (AIF) 的核转位，并且针对 AIF 引入小干扰 RNA (siRNA) 部分保护这些细胞免受 BAY 43-9006 诱导的细胞凋亡。 AIF siRNA 对 A375 细胞几乎没有影响，其中药物诱导的 AIF 释放可以忽略不计。这些数据表明，在敏感细胞系中，BAY 43-9006 诱导的细胞凋亡不依赖于 Bad 去磷酸化和 caspase 激活，并且主要通过 AIF 的核转位介导。
Mitogen-activated protein kinase (MAPK) is activated in the majority of melanomas, and its activity is essential for cell survival. In this report, we examined the effects of a novel raf inhibitor BAY 43-9006 on melanoma cell viability and intracellular signaling and found that it induces apoptosis through a caspase-independent mechanism. At concentrations that suppress extracellular signal-regulated kinase (ERK) phosphorylation, BAY 43-9006 dephosphorylates Bad on Ser(75) and Ser(99), activates Bak and Bax, and reduces the mitochondrial transmembrane potential. BAY 43-9006 (sor-afenib) down-modulates the levels of Bcl-2 and Bcl-X-L, in a MAPK-independent manner in A2058 and SKMEL5 melanoma cells but not in the more resistant A375 cells. Of the three lines tested, only A375 cells were rescued from BAY 43-9006-induced apoptosis by knocking down Bad. BAY 43-9006 induced poly(ADP-ribose) polymerase cleavage and the mitochondrial release of cytochrome c and SMAC. However, the pan-caspase inhibitor Z-VAD-fmk had only a modest protective effect against the drug, suggesting that BAY 439006-induced apoptosis is largely caspase independent. BAY 43-9006 but not the MAP/ERK kinase inhibitors PD98059 or U0126 induced the nuclear translocation of apoptosis-inducing factor (AIF) in A2058 and SKMEL5 cells, and the introduction of a small interfering RNA (siRNA) for AIF partially protected these cells from BAY 43-9006-induced apoptosis. The AIF siRNA had little effect in A375 cells, in which drug-induced AIF release was negligible. These data indicate that in sensitive cell lines, BAY 43-9006-induced apoptosis is independent of Bad dephosphorylation and caspase activation and largely mediated through the nuclear translocation of AIF.