TNF‐related apoptosis‐inducing ligand (TRAIL) induces apoptosis selectively in cancer cells. For melanoma, the targeting of TRAIL signaling appears highly attractive, due to pronounced TRAIL receptor expression in tumor tissue. However, mechanisms of TRAIL resistance observed in melanoma cells may limit its clinical use. The Bcl‐2 family members are critical regulators of cell‐intrinsic apoptotic pathways. Thus, the antiapoptotic Bcl‐2 protein myeloid cell leukemia 1 (Mcl‐1) is overexpressed in many tumor types and was linked to chemotherapy resistance in melanoma. In this study, we evaluated the involvement of antiapoptotic Bcl‐2 proteins (Bcl‐2, Bcl‐x_L, Bcl‐w, Mcl‐1, Bcl‐A1, and Bcl‐B) in TRAIL resistance. They were targeted by small interfering RNA‐mediated silencing in TRAIL‐sensitive (A‐375, Mel‐HO) and in TRAIL‐resistant melanoma cell lines (Mel‐2a, MeWo). This highlighted Mcl‐1 as the most efficient target to overcome TRAIL resistance. In this context, we investigated the effects of Mcl‐1‐targeting microRNAs as well as the Mcl‐1‐selective inhibitor S63845. Both miR‐193b and S63845 resulted in significant enhancement of TRAIL‐induced apoptosis, associated with decreased cell viability. Apoptosis induction was mediated by caspase‐3 processing as well as by Bax and Bak activation, indicating the critical involvement of intrinsic apoptosis pathways. These data may indicate a high relevance of Mcl‐1 targeting also in melanoma therapy. Furthermore, the data may suggest to consider the use of the tumor suppressor miR‐193b as a strategy for countering TRAIL resistance in melanoma.

中文翻译：

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Mcl-1靶向策略可释放TRAIL在黑色素瘤细胞中的凋亡潜力。

TNF相关凋亡诱导配体（TRAIL）选择性诱导癌细胞凋亡。对于黑素瘤，由于在肿瘤组织中明显的TRAIL受体表达，因此TRAIL信号转导的靶向表现出很高的吸引力。但是，在黑素瘤细胞中观察到的TRAIL抗性机制可能会限制其临床应用。Bcl-2家族成员是细胞内凋亡途径的关键调节剂。因此，抗凋亡的Bcl-2蛋白髓样细胞白血病1（Mcl-1）在许多肿瘤类型中均过表达，并且与黑色素瘤的化疗耐药性相关。在这项研究中，我们评估了抗凋亡Bcl-2蛋白（Bcl-2，Bcl-x _L，Bcl-w，Mcl-1，Bcl-A1和Bcl-B）的TRAIL电阻。在TRAIL敏感（A-375，Mel-HO）和TRAIL耐药性黑素瘤细胞系（Mel-2a，MeWo）中，RNA介导的小干扰沉默使其成为靶向。这突出了Mcl-1是克服TRAIL抗性的最有效目标。在这种情况下，我们研究了靶向Mcl-1的microRNA以及Mcl-1选择性抑制剂S63845的作用。miR-193b和S63845均可显着增强TRAIL诱导的凋亡，并降低细胞活力。凋亡诱导是通过caspase-3加工以及Bax和Bak激活介导的，表明内在凋亡通路的关键参与。这些数据可能表明在黑色素瘤治疗中，Mcl-1靶向的相关性也很高。此外，