Genistein sensitizes human hepatocellular carcinoma cells to TRAIL-mediated apoptosis by enhancing Bid cleavage.
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.
Jin
Cheng-Yun
CY
Department of Biomaterial Control (BK21 program), Dongeui University Graduate School, South Korea.
Park
Cheol
C
Moon
Sung-Kwon
SK
Kim
Gi-Young
GY
Kwon
Taeg Kyu
TK
Lee
Su Jae
SJ
Kim
Wun-Jae
WJ
Choi
Yung Hyun
YH
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D019833:Genistein; D020169:Caspases; D020782:Matrix Metalloproteinases