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Research Articles: Therapeutics, Targets, and Development

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

Departments of ¹ Medicine and ² Pathology, The University of Hong Kong, Hong Kong and ³ Department of Gastroenterology, Peking University First Hospital, Beijing, People’s Republic of China

Requests for reprints: Benjamin C.Y. Wong, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong. Phone: 852-28555995; Fax: 852-29049443. E-mail: bcywong{at}hku.hk

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 (PPAR) has been shown to exert proapoptotic and antiproliferative effects in many cancer cell types. However, neither XIAP down-regulation alone nor monotherapy using PPAR ligands is potent enough to control colon cancer. We explored whether XIAP inhibition and PPAR activation offer a synergistic anticancer effect in colon cancer. HCT116-XIAP^+/+ and HCT116-XIAP^-/- cells were treated with troglitazone or 15-deoxy-^12,14-prostaglandin J₂ (15-PGJ₂). 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-PGJ₂-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(ADP-ribose) polymerase, which were more profound in HCT116-XIAP^-/- cells. Pretreatment of cells with XIAP inhibitor 1396-12 also sensitized HCT116-XIAP^+/+ cells to PPAR 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 ligand-induced apoptosis and inhibition of cell proliferation. Thus, simultaneous inhibition of XIAP and activation of PPAR may have a synergistic antitumor effect against colon cancer. [Mol Cancer Ther 2008;7(7):2203–11]

Grant support: Seed Funding Programme for Basic Research of the University of Hong Kong grant 10206827.49710.20600.302.01.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Our unpublished data.

Received 4/ 9/08; revised 5/10/08; accepted 5/18/08.