Down-regulation of X-linked inhibitor of apoptosis synergistically enhanced peroxisome proliferator-activated receptor gamma 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 (PPARgamma) has been shown to exert proapoptotic and antiproliferative effects in many cancer cell types. However, neither XIAP down-regulation alone nor monotherapy using PPARgamma ligands is potent enough to control colon cancer. We explored whether XIAP inhibition and PPARgamma 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-PGJ(2)-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 PPARgamma 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 PPARgamma ligand-induced apoptosis and inhibition of cell proliferation. Thus, simultaneous inhibition of XIAP and activation of PPARgamma may have a synergistic antitumor effect against colon cancer.
Qiao
Liang
L
Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
Dai
Yun
Y
Gu
Qing
Q
Chan
Kwok Wah
KW
Zou
Bing
B
Ma
Juan
J
Wang
Jide
J
Lan
Hui Y
HY
Wong
Benjamin C Y
BC
D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008024:Ligands; D047495:PPAR gamma / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
C477819:15-deoxyprostaglandin J2; D002839:Chromans; D019394:Ki-67 Antigen; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; D051636:X-Linked Inhibitor of Apoptosis Protein; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; D000077288:Troglitazone; D015230:Prostaglandin D2