Sulindac sulfide induces autophagic death in gastric epithelial cells via survivin down-regulation: a mechanism of NSAIDs-induced gastric injury

Biochem Pharmacol. 2011 Jun 1;81(11):1317-23. doi: 10.1016/j.bcp.2011.03.019. Epub 2011 Mar 30.

Abstract

Sulindac sulfide, a nonsteroidal anti-inflammatory drug (NSAID), has anti-tumorigenic and anti-inflammatory activities, but causes gastric mucosal damage. NSAIDs cause gastric injury in part by down-regulation of Survivin, an apoptosis inhibitor, resulting in apoptosis induction. Autophagy is a process that promotes cellular health by destroying unwanted cellular materials. Excessive autophagy induction could lead to a non-apoptotic cell death (autophagic cell death). The present study showed that sulindac sulfide at a physiological concentration also induces autophagic death in human gastric epithelial AGS and rat gastric epithelial RGM-1 cells, and that Survivin down-regulation is a mechanism involved: Sulindac sulfide treatment increased LC3b-II and APG7 levels and cytosolic vacuole formation, indications of autophagy induction, in AGS and RGM-1 cells. Sulindac sulfide treatment induced AGS and RGM-1 cell death, which was significantly reduced by pretreatment with the autophagy inhibitors 3-methyladenine and chloroquine, indicating that sulindac sulfide induced autophagic cell death. Stable overexpression of Survivin in RGM-1 cells did not inhibit the induction of LC3b-II levels or vacuole formation by sulindac sulfide, but significantly reduced the resulting cell death, suggesting that Survivin may inhibit autophagic cell death downstream of LC3b-II induction and vacuole formation. Indeed, siRNA depletion of LC3b in AGS cells inhibited the down-regulation of Survivin levels and the induction of cell death by sulindac sulfide, confirming that down-regulation of Survivin occurs in the autophagy pathway downstream of LC3b-II induction by sulindac sulfide. Induction of Survivin-dependent autophagic cell death is a novel mechanism by which sulindac sulfide induces gastric mucosal injury.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Autophagy / drug effects*
  • Blotting, Western
  • Cell Death / drug effects*
  • Cell Line
  • Down-Regulation / drug effects*
  • Flow Cytometry
  • Gastric Mucosa / cytology
  • Gastric Mucosa / drug effects*
  • Gastric Mucosa / metabolism
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism*
  • RNA, Small Interfering
  • Rats
  • Sulindac / analogs & derivatives*
  • Sulindac / pharmacology
  • Survivin

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • RNA, Small Interfering
  • Survivin
  • Sulindac
  • sulindac sulfide