Eupafolin enhances TRAIL-mediated apoptosis through cathepsin S-induced down-regulation of Mcl-1 expression and AMPK-mediated Bim up-regulation in renal carcinoma Caki cells
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Min Ae Han1,*, Kyoung-jin Min1,*, Seon Min Woo1, Bo Ram Seo1, Taeg Kyu Kwon1
1Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu 704-701, South Korea
*These authors have contributed equally to this work
Taeg Kyu Kwon, email: email@example.com
Keywords: eupafolin, TRAIL, Mcl-1, cathepsin S, AMPK
Received: May 16, 2016 Accepted: August 13, 2016 Published: August 25, 2016
Eupafolin, a flavone found in Artemisia princeps, has been reported for its anti-tumor activity in several cancer cells. In this study, we examined whether eupafolin could sensitize TRAIL-mediated apoptosis in human renal carcinoma Caki cells. We found that eupafolin alone and TRAIL alone had no effect on apoptosis. However, combined treatment with eupafolin and TRAIL markedly induced apoptosis in human renal carcinoma (Caki) cells, glioma cells (U251MG), and prostate cancer cells (DU145), but not normal cells [mesangial cells (MC) and normal mouse kidney cells (TCMK-1)]. Eupafolin induced down-regulation of Mcl-1 expression at the post-translational levels in cathepsin S-dependent manner, and over-expression of Mcl-1 markedly blocked apoptosis induced by combined treatment with eupafolin and TRAIL. In addition, eupafolin increased Bim expression at the post-translational levels via AMP-activated protein kinase (AMPK)-mediated inhibition of proteasome activity. Knock-down of Bim expression by siRNA inhibited eupafolin plus TRAIL-induced apoptosis. Furthermore, combined treatment with eupafolin and TRAIL reduced tumor growth in xenograft models. Taken together, these results suggest that eupafolin enhanced TRAIL-mediated apoptosis via down-regulation of Mcl-1 and up-regulation of Bim in renal carcinoma Caki cells.
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