TY - JOUR
T1 - Down-regulation of c-FLIP contributes to the sensitization effect of 3,3′-diindolylmethane on TRAIL-induced apoptosis in cancer cells
AU - Zhang, Siyuan
AU - Shen, Han Ming
AU - Ong, Choon Nam
PY - 2005/12
Y1 - 2005/12
N2 - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, which has been shown to preferentially induce apoptosis in cancer cells without adverse effects on normal cells. However, there are still some cancer cells, especially those with high malignancy, resistant to TRAIL-induced apoptosis, impeding the clinical anticancer efficiency of TRAIL. In this report, we showed that 3,3′-diindolylmethane, an indole compound derived from cruciferous vegetables, is capable of overcoming TRAIL resistance by sensitizing TRAIL-induced apoptosis in human cancer cells. Noncytotoxic concentrations of 3,3′-diindolylmethane significantly enhanced TRAIL-resistant cancer cells to TRAIL-induced apoptosis via promoting the caspase cascade, a process independent of nuclear factor-κB activation and cell surface TRAIL receptor expression. In the search of the molecular mechanisms involved in the sensitization activity of 3,3′-diindolylmethane, we found that combined treatment of 3,3′-diindolylmethane and TRAIL led to significant down-regulation of the cellular FLICE inhibitory protein expression (c-FLIP). Furthermore, we provided evidence showing that the reduced c-FLIP level is predominately mediated by the ubiquitin-proteasome degradation system. These findings reveal a novel anticancer property of 3,3′-diindolylmethane and suggest that this compound could have potential use in cancer therapy to overcome TRAIL resistance.
AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, which has been shown to preferentially induce apoptosis in cancer cells without adverse effects on normal cells. However, there are still some cancer cells, especially those with high malignancy, resistant to TRAIL-induced apoptosis, impeding the clinical anticancer efficiency of TRAIL. In this report, we showed that 3,3′-diindolylmethane, an indole compound derived from cruciferous vegetables, is capable of overcoming TRAIL resistance by sensitizing TRAIL-induced apoptosis in human cancer cells. Noncytotoxic concentrations of 3,3′-diindolylmethane significantly enhanced TRAIL-resistant cancer cells to TRAIL-induced apoptosis via promoting the caspase cascade, a process independent of nuclear factor-κB activation and cell surface TRAIL receptor expression. In the search of the molecular mechanisms involved in the sensitization activity of 3,3′-diindolylmethane, we found that combined treatment of 3,3′-diindolylmethane and TRAIL led to significant down-regulation of the cellular FLICE inhibitory protein expression (c-FLIP). Furthermore, we provided evidence showing that the reduced c-FLIP level is predominately mediated by the ubiquitin-proteasome degradation system. These findings reveal a novel anticancer property of 3,3′-diindolylmethane and suggest that this compound could have potential use in cancer therapy to overcome TRAIL resistance.
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U2 - 10.1158/1535-7163.MCT-05-0249
DO - 10.1158/1535-7163.MCT-05-0249
M3 - Article
C2 - 16373712
AN - SCOPUS:30344487587
SN - 1535-7163
VL - 4
SP - 1972
EP - 1981
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 12
ER -