Survivin: a novel target for indomethacin-induced gastric injury.
OBJECTIVE
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal erosions and ulcers. Apoptosis is one of the mechanisms. The role of survivin, an antiapoptosis protein, in NSAID-induced gastric injury is unknown. We examined the role of survivin in NSAID-induced gastric mucosal and gastric cell injury.


METHODS
We examined: (1) the effects of indomethacin (nonselective NSAID), celecoxib and NS-398 (cyclooxygenase [COX]-2-selective NSAIDs), SC-560 (a COX-1-selective NSAID), and SC-560 plus celecoxib on survivin expression and extent of injury in rat gastric mucosa; (2) the effects of indomethacin, NS-398, SC-560, and SC-560 plus NS-398 on survivin expression and injury in gastric epithelial (RGM-1) cells; and (3) the effects of survivin suppression with small interfering RNA (siRNA) on RGM-1 cell integrity at baseline and following indomethacin injury.


RESULTS
Indomethacin treatment dose-dependently reduced survivin protein levels and caused severe injury of gastric mucosa and RGM-1 cells. Suppression of survivin expression with siRNA in RGM-1 cells caused cell damage and increased susceptibility to injury by indomethacin. Celecoxib treatment caused exfoliation of the mucosal surface epithelium, but neither caused deep erosions or altered survivin expression. Neither NS-398 nor SC-560 treatment altered survivin levels or produced injury in vivo or in vitro. COX-1 and COX-2 inhibitor combination caused injury in vivo and in vitro but did not decrease survivin expression.


CONCLUSIONS
(1) Indomethacin, but not selective COX-1 or COX-2 inhibitors alone or in combination, reduces survivin expression in gastric mucosal cells and (2) significant reduction of survivin precedes greater severity of gastric injury.
Chiou
Shiun-Kwei
SK
Department of Medicine, Gastroenterology Section, Veterans Affairs Medical Center, 5901 East 7th Street, Long Beach, CA 90822, USA. skchiou@yahoo.com
Tanigawa
Tetsuya
T
Akahoshi
Tomohiko
T
Abdelkarim
Basim
B
Jones
Michael K
MK
Tarnawski
Andrzej S
AS
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D015232:Dinoprostone / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects*; D007213:Indomethacin / Q000009:adverse effects / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000187:drug effects* / Q000502:physiology; D009363:Neoplasm Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D013272:Stomach Diseases / Q000139:chemically induced / Q000503:physiopathology; D013276:Stomach Ulcer / Q000139:chemically induced / Q000503:physiopathology; D000077022:Survivin
D000894:Anti-Inflammatory Agents, Non-Steroidal; C107489:BIRC5 protein, human; D016861:Cyclooxygenase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D015232:Dinoprostone; D007213:Indomethacin