beta-Ionone (ION), an end-ring analogue of beta-
carotenoid, has been known to inhibit
tumor cell growth and induce apoptosis in various types of
cancer cells. Nevertheless, its apoptosis-related molecular mechanisms remain unclear. Here, we first investigated the molecular mechanisms by which ION sensitizes
cancer cells to the therapeutic potential of
tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL). Notably, treatment with subtoxic concentrations of ION and TRAIL effectively inhibited cell viability in the
hepatocellular carcinoma cell line Hep3B and other
cancer cell lines such as colon
carcinoma cell line HCT116 and
leukemia cell line U937. Combined treatment with ION and TRAIL was also more effective in inducing DR5 expression,
caspase activities, and apoptosis than treatment with either agent alone. ION-mediated sensitization to TRAIL was efficiently reduced by treatment with a chimeric blocking antibody or
small interfering RNA specific for DR5. Electrophoretic mobility shift assay and a
chromatin immunoprecipitation assay confirmed that ION treatment upregulates the binding of
transcription factor Sp1 to its putative site within the DR5 promoter region, suggesting that Sp1 is an ION-responsive
transcription factor. In addition, ION significantly increased
hepatocellular carcinoma cell sensitivity to TRAIL by abrogating TRAIL-induced
NF-kappaB activation and decreasing the expression of antiapoptotic
proteins such as XIAP and IAP-1/2. Taken together, these data suggest that ION is a useful agent for TRAIL-based
cancer treatments. Mol
Cancer Ther; 9(4); 833-43. (c)2010 AACR.