Down-regulation of X-linked inhibitor of apoptosis synergistically enhanced peroxisome proliferator-activated receptor γ ligand-induced growth inhibition in colon cancer

We found previously that X-linked inhibitor of apoptosis protein (XIAP), a potent endogenous inhibitor of apoptosis, is overexpressed in colon cancer. Ligand-induced activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to exert proapoptotic and antiproliferative effects in many cancer cell types. However, neither XIAP down-regulation alone nor monotherapy using PPAR gamma ligands is potent enough to control colon cancer. We explored whether XIAP inhibition and PPARy activation offer a synergistic anticancer effect in colon cancer. HCT116-XIAP(+/+) and HCT116-XIAP(-/-) cells were treated with troglitazone or 15-deoxy-Delta(12,14)- prostaglandin J(2) (15-PGJ(2)). Cell growth and apoptosis were measured. Nude mice were s.c. inoculated with HCT116 cells with or without oral troglitazone. Tumor growth, angiogenesis, and apoptosis were measured. Troglitazone- and 15-PGJ(2)-induced growth inhibition and apoptosis were more prominent in HCT116-XIAP(-/-) cells. Troglitazone- and 15-PGJ2-induced apoptosis correlated with enhanced cleavage of caspases and poly(ADPribose) polymerase, which were more profound in HCT116-XIAP(-/-) cells. Pretreatment of cells with XIAP inhibitor 1396-12 also sensitized HCT116-XIAP(+/+) cells to PPAR gamma ligand-induced apoptosis. Troglitazone significantly retarded the growth of xenograft tumors, more significantly so in HCT116-XIAP(-/-) cell-derived tumors. Reduction of tumor size was associated with reduced expression of Ki-67, vascular endothelial growth factor, and CD31 as well as increased apoptosis. Loss of XIAP significantly sensitized colorectal cancer cells to PPAR gamma ligand-induced apoptosis and inhibition of cell proliferation. Thus, simultaneous inhibition of XIAP and activation of PPAR gamma may have a synergistic antitumor effect against colon cancer.