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

Abstract

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 γ (PPARγ) has been shown to exert proapoptotic and antiproliferative effects in many cancer cell types. However, neither XIAP down-regulation alone nor monotherapy using PPARγ ligands is potent enough to control colon cancer. We explored whether XIAP inhibition and PPARγ activation offer a synergistic anticancer effect in colon cancer. HCT116-XIAP +/+ and HCT116-XIAP -/- cells were treated with troglitazone or 15-deoxy-Δ 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-PGJ 2-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 PPARγ 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 PPARγ ligand-induced apoptosis and inhibition of cell proliferation. Thus, simultaneous inhibition of XIAP and activation of PPARγ may have a synergistic antitumor effect against colon cancer. Copyright © 2008 American Association for Cancer Research.