Roles of survivin isoforms in the chemopreventive actions of NSAIDS on colon cancer cells.
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.
Mandayam
Sarathy
S
Division of Gastroenterology, VA Medical Center, 5901 E. Seventh Street-111, Long Beach, CA 90822, USA.
Huang
Richard
R
Tarnawski
Andrzej S
AS
Chiou
Shiun-Kwei
SK
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
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