Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors.
Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors.
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DOI：
10.18632/oncotarget.7790
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Kluza J
中科院分区：
文献类型：
--
作者：
Corazao-Rozas P;Guerreschi P;André F;Gabert PE;Lancel S;Dekiouk S;Fontaine D;Tardivel M;Savina A;Quesnel B;Mortier L;Marchetti P;Kluza J
尽管 MAPK 通路抑制剂正在成为一种有前景的抗癌策略，但它们不足以完全消除癌细胞，而且其对 BRAF 突变黑色素瘤患者的长期疗效也非常有限。众所周知，BRAF 抑制剂 (BRAFi) 在细胞死亡出现之前会阻碍葡萄糖的摄取。在这里，我们表明 BRAFi 诱导线粒体的广泛重组，包括线粒体活性的增加以及与线粒体网络重塑相关的生物发生。此外，我们报告了暴露于 BRAFi 的黑色素瘤中 ER 和线粒体之间的密切相互作用。这种物理连接有利于线粒体 Ca2+ 从内质网释放后的吸收。有趣的是，在体外和体内暴露于 BRAFi 的细胞中，Mfn2 沉默会破坏 ER-线粒体界面，加剧 ER 应激并加剧 ER 应激诱导的细胞凋亡。这种线粒体对 ER 应激介导的细胞死亡的控制在暴露于 MEK 抑制剂的 BRAF 和 NRAS 突变黑色素瘤细胞中是相似的。这一证据强化了将 MAPK 通路抑制剂与线粒体药物相结合以改善靶向治疗的相关性。
Although MAPK pathway inhibitors are becoming a promising anticancer strategy, they are insufficient to fully eliminate cancer cells and their long-term efficacy is strikingly limited in patients with BRAF-mutant melanomas. It is well established that BRAF inhibitors (BRAFi) hamper glucose uptake before the apparition of cell death. Here, we show that BRAFi induce an extensive restructuring of mitochondria including an increase in mitochondrial activity and biogenesis associated with mitochondrial network remodeling. Furthermore, we report a close interaction between ER and mitochondria in melanoma exposed to BRAFi. This physical connection facilitates mitochondrial Ca2+ uptake after its release from the ER. Interestingly, Mfn2 silencing disrupts the ER–mitochondria interface, intensifies ER stress and exacerbates ER stress-induced apoptosis in cells exposed to BRAFi in vitro and in vivo. This mitochondrial control of ER stress-mediated cell death is similar in both BRAF- and NRAS-mutant melanoma cells exposed to MEK inhibitors. This evidence reinforces the relevance in combining MAPK pathway inhibitors with mitochondriotropic drugs to improve targeted therapies.
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Mootha, Vamsi K.
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作者：
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