Loss of XIAP sensitizes colon cancer cells to PPARgamma independent antitumor effects of troglitazone and 15-PGJ2.
We investigated whether the anticancer effect of a combination of XIAP down-regulation and PPAR gamma activation on colon cancer is PPARgamma receptor dependent. HCT116-XIAP(+/+) cells and HCT116-XIAP(-/-) cells were treated with troglitazone or 15-deoxy-Delta(12,14)-prostaglandin J2 (15-PGJ2) with or without prior exposure to PPARgamma inhibitor GW9662. Cell proliferation and apoptosis was evaluated. Athymic mice carrying HCT116-XIAP(-/-) cells-derived tumors were treated with troglitazone in the presence or absence of GW9662. Inhibition of cell proliferation and induction of apoptosis by troglitazone and 15-PGJ2 were more prominent in HCT116-XIAP(-/-) cells. PPARgamma ligand-induced growth inhibition, apoptosis, caspase and PARP cleavage could not be blocked by GW9662. Troglitazone significantly retarded growth of xenograft tumors and this effect was not blocked by GW9662. Marked apoptosis and an up-regulation of E-cadherin were observed in xenograft tumor tissues, and GW9662 did not affect these effects. Thus, a combination of XIAP down-regulation and PPARgamma ligands exert a significant anticancer effect in colon cancer via a PPARgamma independent pathway.
Qiao
Liang
L
Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong.
Dai
Yun
Y
Gu
Qing
Q
Chan
Kwok Wah
KW
Ma
Juan
J
Lan
H Y
HY
Zou
Bing
B
Rocken
Christoph
C
Ebert
Matthias P A
MP
Wong
Benjamin C Y
BC
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015536:Down-Regulation; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D047495:PPAR gamma / Q000032:analysis / Q000502:physiology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*
C477819:15-deoxyprostaglandin J2; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000970:Antineoplastic Agents; D002839:Chromans; D047495:PPAR gamma; D045162:Thiazolidinediones; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020169:Caspases; D000077288:Troglitazone; D015230:Prostaglandin D2