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

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.