Tumor necrosis factor-related apoptosis ligand (TRAIL) represents a promising cancer therapeutic agent considering its selectivity in targeting malignant cells while sparing normal cells. However, hepatocellular carcinoma (HCC) cells are intrinsically resistant to TRAIL, in part, due to the compensatory activation of nuclear factor-kappaB (NF-κB). Previously, based on the scaffold of indole-3-carbinol, we developed a potent Akt/NF-κB signaling inhibitor, OSU-A9, that exhibits in vitro and in vivo efficacy in suppressing HCC cell growth.
In this study, we report the sensitizing effect of OSU-A9 on TRAIL-induced cell death in Hep3B and Huh7 HCC cells by antagonizing TRAIL-induced NF-κB activation. Even at 1 μM, OSU-A9 could restore the sensitivity of these cells to TRAIL-mediated antitumor effect to a level comparable to that of TRAIL-sensitive PC-3 cells. Exposure to OSU-A9 led to a dose-dependent reduction in the expression and nuclear localization of RelA/p65 by suppressing Akt activation and RelA expression, which was accompanied by parallel decreases in the expression of antiapoptotic Bcl-xL, Mcl-1, cIAP1, cIAP2, and survivin. In addition, OSU-A9 upregulated death receptor (DR)5 expression via a reactive oxygen species-dependent mechanism. Concertedly, these effects gave rise to increased capsase-3 and caspase-8 activities and PARP cleavage in TRAIL-treated cells, indicative of therapeutic synergy between OSU-A9 and TRAIL. Moreover, this synergistic effect was abolished by the ectopic expression of NF-κB/p65, supporting the role of NF-κB inhibition in OSU-A9-mediated sensitization of HCC cells to TRAIL. Taken together, the ability of OSU-A9 to accentuate TRAIL-induced apoptosis by inactivating NF-κB signaling might foster a promising therapeutic strategy for HCC.
|Journal||Clinical Cancer Research|
|Publisher||American Association for Cancer Research (AACR)|