Volasertib Enhances Sensitivity to TRAIL in Renal Carcinoma Caki Cells through Downregulation of c-FLIP Expression.

Mi-Yeon Jeon,Jong-Wook Park,Taeg Kwon,Seon Woo,Shin Kim,Seung Seo,Kyoung-Jin Min

doi:10.3390/ijms18122568

Mi-Yeon Jeon, Jong-Wook Park + Show 5 more

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https://doi.org/10.3390/ijms18122568

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Abstract

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.

Highlights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in a multiple of cancer cells, but tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has no effect on the apoptosis of normal cells [1,2]
We show here for the first time that downregulation of cellular-FLICE-inhibitory protein (c-FLIP) expression is a major role in sensitizing effect of volasertib on TRAIL-induced apoptosis in cancer cells
Overexpression of c-FLIP attenuated combined treatment-induced apoptosis and poly (ADP-ribose) polymerase (PARP) cleavage (Figure 4C). These results suggest that the downregulation of c-FLIP expression is an important role in the combined treatment of volasertib and TRAIL-induced apoptosis

Summary

Introduction

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in a multiple of cancer cells, but TRAIL has no effect on the apoptosis of normal cells [1,2]. Treatment with TRAIL may be insufficient for cancer therapy because some cancer cells are resistant to the apoptotic effects of TRAIL [3,4]. TRAIL-resistant cancer cells can be sensitized by cancer chemopreventive agents, suggesting that combined treatment may be a possibility. Elevated levels of PLK1 have been reported in multiple cancer types, including melanoma, prostate, breast, colorectal, and renal cancer [6,7]. Volasertib (BI 6727) is a PLK1 inhibitor [9] and has been reported as a potential therapeutic agent in multiple cancer types. PLK1 inhibitor-resistant cell lines have been reported [10]. Whether volasertib has sensitizing effects against TRAIL-mediated apoptotic cell death remains unclear

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