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

Abstract

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.

Combining naturally occurring polyphenols with TNF-related apoptosis-inducing ligand: a promising approach to kill resistant cancer cells?

“…This amplification loop is negatively controlled by anti-apoptotic members of the Bcl-2 family and is heavily dependent on Bax [30], in type II cells [31]. TRAIL-induced apoptosis can also be negatively regulated by other intracellular factors including cellular inhibitor of apoptosis protein (cIAP), X-linked IAP (XIAP) or survivin, downstream of Methyldihydroquercetin BB-1 [70] Kaempferol [71,73] Myricetin [74] Flavanones ND Flavones Apigenin [75,76] Luteolin [77,78] Wogonin [79,80,82] Baicalein [84] Flavopyridol (semi-synthetic flavone) [125][126][127][128][129][130] Isoflavones Genistein [86][87][88][89][90][91][92] Daidzein [93] Chalcones…”

Gli2 silencing enhances TRAIL-induced apoptosis and reduces tumor growth in human hepatoma cells in vivo

“…SMMC-7721-shRNA, SMMC-7721-NC, and SMMC-7721(1 £ 10 6 ) were implanted subcutaneously into the right flank of mice. After 1 week, TRAIL (50 ng/mouse) was injected into the peritoneal space at days 1,4,8,11,15, and 18, respectively. Each group consisted of 5 mice, PBS treatment were used as control groups.…”

“…The sensitivity of cancer cells to TRAIL can be increased by combining TRAIL with compounds which can reduce the expression level of c-FLIP or Bcl-2. [7][8][9] At present, the XIAP antagonist, Smac analog, and the Bcl-2 antagonist, BH3 analog, either alone or in combination have been studied. [10][11][12] However, there is no report on c-FLIP antagonist.…”

Cancer Chemopreventive and Therapeutic Potential of Guggulsterone

“…However, many tumors possess TRAIL resistance that can be reversed by combination therapy [89][90][91][92]. Several agents sensitize HCC cells to TRAIL-induced apoptosis via a STAT3-mediated DR5-dependent mechanism [93,94] or through NF-kB-dependent inhibition of COX-2 expression [95].…”