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

Area of Science:

• Molecular Biology
• Oncology
• Pharmacology

Background:

• Gastric cancer (GC) is a significant global health challenge requiring novel therapeutic targets.
• Mitochondrial deacetylase Sirtuin 3 (SIRT3) plays a role in cancer progression and is a potential therapeutic target.

Purpose of the Study:

• To investigate the effect of indomethacin on gastric cancer cell growth.
• To elucidate the mechanism by which indomethacin affects gastric cancer, focusing on SIRT3.

Main Methods:

• In vitro studies using human gastric adenocarcinoma cells.
• Interaction studies to determine indomethacin's binding site on SIRT3.
• Meta-analysis of The Cancer Genome Atlas (TCGA) data.
• Transcriptome sequencing.
• Western blotting and assessment of mitochondrial function markers.

Main Results:

• Indomethacin competitively inhibits SIRT3 by binding to its nicotinamide adenine dinucleotide (NAD)-binding site.
• High SIRT3 expression correlates with poor prognosis in gastric cancer patients.
• Indomethacin treatment downregulates SIRT3, leading to increased acetylation of SOD2 and OGG1.
• This disruption causes mitochondrial dysfunction, mtDNA damage, and apoptosis via the AMPK/PGC1α/SIRT3 axis.

Conclusions:

• Indomethacin effectively arrests gastric cancer cell growth by targeting and downregulating SIRT3.
• Disruption of the SIRT3 signaling pathway by indomethacin induces mitochondrial dysfunction and apoptosis in gastric cancer cells.
• Indomethacin represents a potential therapeutic agent for gastric cancer by targeting SIRT3.