iScience (Apr 2024)

NSAID targets SIRT3 to trigger mitochondrial dysfunction and gastric cancer cell death

  • Subhashis Debsharma,
  • Saikat Pramanik,
  • Samik Bindu,
  • Somnath Mazumder,
  • Troyee Das,
  • Uttam Pal,
  • Debanjan Saha,
  • Rudranil De,
  • Shiladitya Nag,
  • Chinmoy Banerjee,
  • Nakul Chandra Maiti,
  • Zhumur Ghosh,
  • Uday Bandyopadhyay

Journal volume & issue
Vol. 27, no. 4
p. 109384

Abstract

Read online

Summary: Gastric cancer (GC) is a deadly malignancy that demands effective therapeutic intervention capitalizing unique drug target/s. Here, we report that indomethacin, a cyclooxygenase non-selective non-steroidal anti-inflammatory drug, arrests GC cell growth by targeting mitochondrial deacetylase Sirtuin 3 (SIRT3). Interaction study revealed that indomethacin competitively inhibited SIRT3 by binding to nicotinamide adenine dinucleotide (NAD)-binding site. The Cancer Genome Atlas data meta-analysis indicated poor prognosis associated with high SIRT3 expression in GC. Further, transcriptome sequencing data of human gastric adenocarcinoma cells revealed that indomethacin treatment severely downregulated SIRT3. Indomethacin-induced SIRT3 downregulation augmented SOD2 and OGG1 acetylation, leading to mitochondrial redox dyshomeostasis, mtDNA damage, respiratory chain failure, bioenergetic crisis, mitochondrial fragmentation, and apoptosis via blocking the AMPK/PGC1α/SIRT3 axis. Indomethacin also downregulated SIRT3 regulators ERRα and PGC1α. Further, SIRT3 knockdown aggravated indomethacin-induced mitochondrial dysfunction as well as blocked cell-cycle progression to increase cell death. Thus, we reveal how indomethacin induces GC cell death by disrupting SIRT3 signaling.

Keywords