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Targeting mitochondria in melanoma: Interplay between MAPK signaling pathway and mitochondrial dynamics

机译:MITANOMA的靶向线粒体:MAPK信号通路与线粒体动力学之间的相互作用

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Melanoma is a malignant proliferative disease originated in melanocytes, characterized by high metastatic activity and by the activation of oncogenes, such as B-RAF (40-60% of cases). Recent studies have shown that vemurafenib (a MAPK inhibitor) promoted disturbance of mitochondrial bioenergetics, although underlying mechanisms are not fully comprehended. Here we showed that MAPK inhibition by vemurafenib in B-RAF(V600E)-mutated human melanoma culminated in the inhibition of DRP1 phosphorylation, associated to a large mitochondrial network remodeling to the hyperfused phenotype, and increased oxidative phosphorylation capacity. Such alterations may be associated to melanoma resistance to vemurafenib, since the impairment of oxidative phosphorylation increased the vemurafenib cytotoxicity. These results point to the potential of mitochondrial dynamics as a targetable pathway in melanoma.
机译:黑色素瘤是一种恶性增殖性疾病,起源于黑素细胞,其特征在于高转移性活性和激活癌基因,例如B-RAF(40-60%的病例)。 最近的研究表明,vemurafenib(MAPK抑制剂)促进了线粒体生物能器的干扰,尽管潜在的机制没有完全理解。 在这里,我们展示了vemureafenib在B-RAF(V600E)的MAPK抑制 - 在抑制DRP1磷酸化中抑制的抑制DRP1磷酸化,与大型线粒体网络重塑到过脱脂表型,并增加氧化磷酸化能力。 由于氧化磷酸化的损害增加了vemureafenib细胞毒性,因此这种改变可能与vemureafenib的抗性相关。 这些结果指出了线粒体动力学的潜力,作为黑素瘤的可靶向途径。

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