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Genistein sensitizes human hepatocellular carcinoma cells to TRAIL-mediated apoptosis by enhancing Bid cleavage

Jin, Cheng-Yuna; Park, Cheolb; Moon, Sung-Kwonc; Kim, Gi-Youngd; Kwon, Taeg Kyue; Lee, Su Jaef; Kim, Wun-Jaeg; Choi, Yung Hyuna b

doi: 10.1097/CAD.0b013e32832e8998

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and it has been shown that many human cancer cell lines are refractory to TRAIL-induced cell death. However, the molecular mechanisms underlying resistance are unclear. In this study, we show that TRAIL resistance is reversed in human hepatoma cells by genistein, an isoflavone found in soy products. Synergistic induction of apoptosis in cells treated with genistein plus TRAIL was associated with cleavage of Bid, a proapoptotic BH3-only protein. Silencing of Bid expression reduced decreases in mitochondrial membrane potential and reduced apoptosis in cells treated with genistein and TRAIL, confirming that Bid cleavage is required for the response. Pretreatment with caspase-3 and caspase-8 inhibitors reduced cotreatment-induced apoptosis. However, treatment with TRAIL alone induced caspase-8 activity that was not different than TRAIL plus genistein; both effectively induced Bid cleavage. These data suggest that genistein abolishes resistance to the Bid cleavage of TRAIL, and that genistein does not interfere with signals upstream of Bid in hepatoma cells.

aDepartment of Biomaterial Control (BK21 program), Dongeui University Graduate School

bDepartment of Biochemistry, Dongeui University College of Oriental Medicine and Blue-Bio Industry RIC, Busan

cDepartment of Food and Biotechnology, Chungju National University, Chungju

dFaculty of Applied Marine Science, Cheju National University, Jeju

eDepartment of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, Taegu

fLaboratory of Molecular Biochemistry, Department of Chemistry, Hanyang University, Seoul

gDepartment of Urology, Chungbuk National University College of Medicine, Cheongju, South Korea

Correspondence to Dr Yung Hyun Choi, PhD, Department of Biochemistry, Dongeui University College of Oriental Medicine, Yangjung-dong, Busanjin-gu, Busan 614-052, South Korea

Tel: +82 51 857413; fax: +82 51 853 4036;


Received 13 March 2009 Revised form accepted 25 May 2009

© 2009 Lippincott Williams & Wilkins, Inc.