Department of Immunology, School of Mediine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, Korea.
Int J Mol Sci. 2017 Nov 29;18(12):2568. doi: 10.3390/ijms18122568.
Polo-like kinase 1 (PLK1) plays major roles in cell cycle control and DNA damage response. Therefore, PLK1 has been investigated as a target for cancer therapy. Volasertib is the second-in class dihydropteridinone derivate that is a specific PLK1 inhibitor. In this study, we examined that combining PLK1 inhibitor with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) would have an additive and synergistic effect on induction of apoptosis in cancer cells. We found that volasertib alone and TRAIL alone had no effect on apoptosis, but the combined treatment of volasertib and TRAIL markedly induced apoptosis in Caki (renal carcinoma), A498 (renal carcinoma) and A549 (lung carcinoma) cells, but not in normal cells (human skin fibroblast cells and mesangial cells). Combined treatment induced accumulation of sub-G1 phase, DNA fragmentation, cleavage of poly (ADP-ribose) polymerase (PARP) and activation of caspase 3 activity in Caki cells. Interestingly, combined treatment induced downregulation of cellular-FLICE-inhibitory protein (c-FLIP) expression and ectopic expression of c-FLIP markedly blocked combined treatment-induced apoptosis. Therefore, this study demonstrates that volasertib may sensitize TRAIL-induced apoptosis in Caki cells via downregulation of c-FLIP.
丝氨酸/苏氨酸激酶 1（PLK1）在细胞周期控制和 DNA 损伤反应中发挥重要作用。因此，PLK1 已被作为癌症治疗的靶点进行研究。沃拉司汀是二氢喋呤衍生物类的第二种，是一种特异性 PLK1 抑制剂。在这项研究中，我们研究了 PLK1 抑制剂与肿瘤坏死因子相关凋亡诱导配体（TRAIL）联合应用对癌细胞凋亡的诱导作用是否具有相加和协同作用。我们发现，沃拉司汀单独使用和 TRAIL 单独使用对细胞凋亡均无影响，但沃拉司汀和 TRAIL 的联合治疗显著诱导了 Caki（肾癌细胞）、A498（肾癌细胞）和 A549（肺癌细胞）细胞的凋亡，而对正常细胞（人皮肤成纤维细胞和肾小球系膜细胞）没有影响。联合治疗诱导 Caki 细胞亚 G1 期积累、DNA 片段化、多聚（ADP-核糖）聚合酶（PARP）的切割和 caspase 3 活性的激活。有趣的是，联合治疗诱导细胞-FLICE 抑制蛋白（c-FLIP）的表达下调，而 c-FLIP 的异位表达则显著阻断了联合治疗诱导的细胞凋亡。因此，本研究表明，沃拉司汀可能通过下调 c-FLIP 来增强 TRAIL 诱导的 Caki 细胞凋亡。
