Magnolol Enhances the Therapeutic Effects of TRAIL through DR5 Upregulation and Downregulation of c-FLIP and Mcl-1 Proteins in Cancer Cells.

Seon Min Woo,Kyoung-Jin Min,Taeg Kyu Kwon

doi:10.3390/molecules25194591

Abstract

Magnolol is a biologically active compound, isolated from the Chinese herb Magnolia, that regulates antiproliferative, anticancer, antiangiogenic and antimetastatic activities. We found that magnolol sensitizes TRAIL-induced apoptotic cell death via upregulation of DR5 and downregulation of cellular FLICE-inhibitory protein (c-FLIP) and Mcl-1 in cancer cells, but not in normal cells. Mechanistically, magnolol increased ATF4-dependent DR5 expression at the transcription level, and knockdown of ATF4 markedly inhibited magnolol-induced DR5 upregulation. Silencing DR5 with siRNA prevented combined treatment with magnolol and TRAIL-induced apoptosis and PARP cleavage. Magnolol induced proteasome-mediated Mcl-1 downregulation, while magnolol-induced c-FLIP downregulation was regulated, at least in part, by lysosomal degradation. Our results revealed that magnolol enhanced TRAIL-induced apoptosis via ATF4-dependent DR5 upregulation and downregulation of c-FLIP and Mcl-1 proteins.

Highlights

Magnolol, a constituent of Magnolia, has been used in traditional Chinese herbal medicines for treating gastrointestinal disorders and allergic diseases [1,2]
We examined the effect of a sublethal concentration of magnolol on the sensitivity to Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in renal carcinoma Caki-1 cells
We examined whether the effect of magnolol on DR5, Mcl-1 and cellular FLICE-inhibitory protein (c-FLIP) expression patterns is restricted to Caki-1 cells

Summary

Introduction

A constituent of Magnolia, has been used in traditional Chinese herbal medicines for treating gastrointestinal disorders and allergic diseases [1,2]. It possesses diverse biological effects, such as anticancer, antiangiogenetic, antioxidative, antimetastatic and neurotrophic [3,4,5,6]. Magnolol has a sensitizing effect on chemotherapeutic-agent-mediated cancer cell death. Magnolol sensitizes death receptor (DR)-mediated death in non-small cell lung cancer [17]. Inactivation of Akt signaling by magnolol enhances the therapeutic effect of sorafenib through downregulation of antiapoptotic proteins in hepatocellular carcinoma in vitro and in vivo [19]. Magnolol could be a potential adjuvant that may sensitize the therapeutic efficiency of anticancer drugs

Methods

Results

Discussion

Conclusion