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

TitleDown-regulation of X-linked inhibitor of apoptosis synergistically enhanced peroxisome proliferator-activated receptor γ ligand-induced growth inhibition in colon cancer
Authors
Issue Date2008
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/
Citation
Molecular Cancer Therapeutics, 2008, v. 7 n. 7, p. 2203-2211 How to Cite?
AbstractWe 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.
Persistent Identifierhttp://hdl.handle.net/10722/163200
ISSN
2015 Impact Factor: 5.579
2015 SCImago Journal Rankings: 3.224
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorQiao, Len_US
dc.contributor.authorDai, Yen_US
dc.contributor.authorGu, Qen_US
dc.contributor.authorKwok, WCen_US
dc.contributor.authorZou, Ben_US
dc.contributor.authorMa, Jen_US
dc.contributor.authorWang, Jen_US
dc.contributor.authorLan, HYen_US
dc.contributor.authorWong, BCYen_US
dc.date.accessioned2012-09-05T05:28:41Z-
dc.date.available2012-09-05T05:28:41Z-
dc.date.issued2008en_US
dc.identifier.citationMolecular Cancer Therapeutics, 2008, v. 7 n. 7, p. 2203-2211en_US
dc.identifier.issn1535-7163en_US
dc.identifier.urihttp://hdl.handle.net/10722/163200-
dc.description.abstractWe 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.en_US
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/en_US
dc.relation.ispartofMolecular Cancer Therapeuticsen_US
dc.titleDown-regulation of X-linked inhibitor of apoptosis synergistically enhanced peroxisome proliferator-activated receptor γ ligand-induced growth inhibition in colon canceren_US
dc.typeArticleen_US
dc.identifier.emailQiao, L:lq8688@hotmail.comen_US
dc.identifier.emailWang, J:jidewang@gmail.comen_US
dc.identifier.emailWong, BCY:bcywong@hku.hken_US
dc.identifier.authorityQiao, L=rp00513en_US
dc.identifier.authorityWang, J=rp00491en_US
dc.identifier.authorityWong, BCY=rp00429en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1158/1535-7163.MCT-08-0326en_US
dc.identifier.scopuseid_2-s2.0-51049118824en_US
dc.identifier.hkuros143050-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-51049118824&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume7en_US
dc.identifier.issue7en_US
dc.identifier.spage2203en_US
dc.identifier.epage2211en_US
dc.identifier.isiWOS:000257964100047-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridQiao, L=7202151719en_US
dc.identifier.scopusauthoridDai, Y=7401512993en_US
dc.identifier.scopusauthoridGu, Q=24469982400en_US
dc.identifier.scopusauthoridKwok, WC=24171150800en_US
dc.identifier.scopusauthoridZou, B=35228257300en_US
dc.identifier.scopusauthoridMa, J=35275386200en_US
dc.identifier.scopusauthoridWang, J=35309087500en_US
dc.identifier.scopusauthoridLan, HY=7102710832en_US
dc.identifier.scopusauthoridWong, BCY=7402023340en_US

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