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Sensitization of human melanoma cells for TRAIL-induced apoptosis by a selective aurora kinase A inhibitor

机译:选择性极光激酶A抑制剂对人黑素瘤细胞的TRAIL诱导的凋亡的敏感性

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Different therapeutic strategies in metastatic melanoma focused on signalling pathways controlling cell proliferation, cell cycle and apoptosis. While TRAIL (TNF-related apoptosis inducing ligand) has been shown to be an interesting candidate for inducing apoptosis in cancer cells without affecting normal cells, the ability of cancer cells to develop resistance, limits its therapeutic potential. Using a recently established experimental A-375 melanoma cell model for investigating TRAIL resistance, we could demonstrate that the aurora kinase A inhibitor Alisertib (MLN 8237) enhances the proapoptotic effects of TRAIL and sensitizes TRAIL-selected melanoma cells with acquired resistance, associated with an activation of intrinsic mitochondrial apoptotic pathways. In course of this activation an upregulation of p53 in the nuclear fraction was shown. Thus, the aurora kinase A inhibitor Alisertib is able to overcome TRAIL-induced resistance in melanoma cells suggesting the combination of TRAIL and Alisertib as a promising therapeutic strategy for metastatic melanoma.
机译:转移性黑色素瘤的不同治疗策略集中于控制细胞增殖,细胞周期和凋亡的信号通路。尽管已经显示TRAIL(TNF相关的凋亡诱导配体)是诱导癌细胞凋亡而不影响正常细胞的有趣候选物,但是癌细胞产生抗性的能力限制了其治疗潜力。使用最近建立的实验性A-375黑色素瘤细胞模型研究TRAIL耐药性,我们可以证明极光激酶A抑制剂Alisertib(MLN 8237)增强TRAIL的促凋亡作用,并使TRAIL选择的黑色素瘤细胞具有获得性耐药性,并与内在的线粒体凋亡途径的激活。在该活化过程中,显示​​了核级分中p53的上调。因此,极光激酶A抑制剂Alisertib能够克服TRAIL诱导的黑色素瘤细胞耐药性,提示TRAIL和Alisertib的联合使用是转移性黑色素瘤的有希望的治疗策略。

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