Department of Medicine, the University of Washington School of Medicine, Seattle, Washington, USA.
PLoS One. 2013 Jul 15;8(7):e69593. doi: 10.1371/journal.pone.0069593. Print 2013.
While the TRAIL pathway represents a promising therapeutic target in melanoma, resistance to TRAIL-mediated apoptosis remains a barrier to its successful adoption. Since the Wnt/β-catenin pathway has been implicated in facilitating melanoma cell apoptosis, we investigated the effect of Wnt/β-catenin signaling on regulating the responses of melanoma cells to TRAIL. Co-treatment of melanoma cell lines with WNT3A-conditioned media and recombinant TRAIL significantly enhanced apoptosis compared to treatment with TRAIL alone. This apoptosis correlates with increased abundance of the pro-apoptotic proteins BCL2L11 and BBC3, and with decreased abundance of the anti-apoptotic regulator Mcl1. We then confirmed the involvement of the Wnt/β-catenin signaling pathway by demonstrating that siRNA-mediated knockdown of an intracellular β-catenin antagonist, AXIN1, or treating cells with an inhibitor of GSK-3 also enhanced melanoma cell sensitivity to TRAIL. These studies describe a novel regulation of TRAIL sensitivity in melanoma by Wnt/β-catenin signaling, and suggest that strategies to enhance Wnt/β-catenin signaling in combination with TRAIL agonists warrant further investigation.
尽管 TRAIL 通路在黑色素瘤中代表了一个有前途的治疗靶点，但对 TRAIL 介导的细胞凋亡的抵抗仍然是其成功应用的障碍。由于 Wnt/β-catenin 通路已被牵涉到促进黑色素瘤细胞凋亡，我们研究了 Wnt/β-catenin 信号对调节黑色素瘤细胞对 TRAIL 反应的影响。与单独用 TRAIL 治疗相比，用 WNT3A 条件培养基和重组 TRAIL 共同处理黑色素瘤细胞系显著增强了细胞凋亡。这种凋亡与促凋亡蛋白 BCL2L11 和 BBC3 的丰度增加以及抗凋亡调节剂 Mcl1 的丰度降低相关。然后，我们通过证明 siRNA 介导的细胞内β-catenin 拮抗剂 AXIN1 的敲低或用 GSK-3 的抑制剂处理细胞也增强了黑色素瘤细胞对 TRAIL 的敏感性，证实了 Wnt/β-catenin 信号通路的参与。这些研究描述了 Wnt/β-catenin 信号对黑色素瘤中 TRAIL 敏感性的新调节，并表明增强 Wnt/β-catenin 信号与 TRAIL 激动剂联合的策略值得进一步研究。
