Maritoclax Enhances TRAIL-Induced Apoptosis via CHOP-Mediated Upregulation of DR5 and miR-708-Mediated Downregulation of cFLIP.

Mi-Yeon Jeon,Seung Seo,Shin Kim,Kyoung-Jin Min,Jong-Wook Park,Seon Woo,Sang Kim,Yung Choi,Tae-Jin Lee,Dong Kim,Taeg Kwon

doi:10.3390/molecules23113030

Abstract

Maritoclax, an active constituent isolated from marine bacteria, has been known to induce Mcl-1 downregulation through proteasomal degradation. In this study, we investigated the sensitizing effect of maritoclax on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. We found that combined treatment with maritoclax and TRAIL markedly induced apoptosis in renal carcinoma (Caki, ACHN and A498), lung cancer (A549) and hepatocellular carcinoma (SK-Hep1) cells. The upregulation of death receptor 5 (DR5) and downregulation of cellular FLICE-inhibitory protein (cFLIP) were involved in maritoclax plus TRAIL-induced apoptosis. Maritoclax-induced DR5 upregulation was regulated by induction of C/EBP homologous protein (CHOP) expression. Interestingly, maritoclax induced cFLIP downregulation through the increased expression of miR-708. Ectopic expression of cFLIP prevented combined maritoclax and TRAIL-induced apoptosis. Taken together, maritoclax sensitized TRAIL-induced apoptosis through CHOP-mediated DR5 upregulation and miR-708-mediated cFLIP downregulation.

Highlights

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered a promising anticancer agent, because it selectively induces apoptotic cell death in cancer cells, but not in normal cells [1,2,3,4]
A Mcl-1 specific inhibitor, could sensitize TRAIL-induced apoptotic cell death in Caki cells
Maritoclax plus TRAIL induced the nuclear condensation and the DNA fragmentation, which is the typical property of apoptosis (Figure 1C,D)

Summary

Introduction

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered a promising anticancer agent, because it selectively induces apoptotic cell death in cancer cells, but not in normal cells [1,2,3,4]. There are several reasons why normal cells are more resistant to TRAIL than cancer cells. One of the reasons is that normal cells highly express decoy death receptors (DcRs), which could interfere with the TRAIL-mediated apoptotic pathway [5]. Single anti-apoptotic protein inhibition or pro-apoptotic proteins induction is enough to induce TRAIL-mediated apoptosis in cancer cells [8,9]. Upregulation of DR5 proteins or downregulation of cFLIP fails to increase TRAIL sensitivity in normal astrocytes [10], and inhibition of both cFLIP and XIAP expression or inhibition of both cFLIP expression and activity of anti-apoptotic Bcl-2 proteins increases TRAIL-induced apoptosis in normal fibroblast [7].

Methods

Results

Conclusion