title: Roles of survivin isoforms in the chemopreventive actions of NSAIDS on colon cancer cells.
abstract: NSAIDs downregulate survivin (an apoptosis inhibitor), increase apoptosis and reduce growth of colon polyps and cancers. Recently, anti- and pro-apoptosis isoforms of survivin were identified. The roles of these isoforms in NSAID-induced colon cancer cell death have not been examined, and is the focus of this study. The anti-apoptosis isoforms, wild-type (WT) survivin and survivin-DeltaEx3, and the pro-apoptosis isoform, survivin-2b, were present in HT-29 and RKO cells. Indomethacin treatment significantly decreased WT survivin and survivin-DeltaEx3 (30.5+/-10.4% and 20.3+/-6.7%, respectively) but not survivin-2b mRNA in RKO cells. In HT-29 cells, all three isoform mRNAs were slightly decreased by indomethacin treatment. Consistently, indomethacin treatment dramatically reduced WT survivin protein in RKO but not HT-29 cells. Indomethacin treatment increased apoptosis and general cell death more significantly in RKO cells (75.7+/-1.1% cell death at 48 h) than in HT-29 cells (25.4+/-3.7% cell death at 48 h). Anti-sense suppression of survivin-2b mRNA increased resistance of both RKO and HT-29 cells to indomethacin. These data support a role for survivin isoforms in colon cancer cell apoptosis, and thus in prevention of colon cancer growth by NSAIDs.
authors.affiliation: Division of Gastroenterology, VA Medical Center, 5901 E. Seventh Street-111, Long Beach, CA 90822, USA.
authors.forename: Sarathy
authors.initials: S
authors.lastname: Mandayam
authors.forename: Richard
authors.initials: R
authors.lastname: Huang
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Tarnawski
authors.forename: Shiun-Kwei
authors.initials: SK
authors.lastname: Chiou
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D012333:RNA, Messenger; D000077022:Survivin; D007213:Indomethacin