NSAID targets SIRT3 to trigger mitochondrial dysfunction and gastric cancer cell death
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224006059 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Subhashis Debsharma |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T20:26:29Z |
| format | Article |
| id | doaj.art-f474bf5178804b12befd7ffeeced126b |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-24T20:26:29Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-f474bf5178804b12befd7ffeeced126b2024-03-22T05:40:23ZengElsevieriScience2589-00422024-04-01274109384NSAID targets SIRT3 to trigger mitochondrial dysfunction and gastric cancer cell deathSubhashis Debsharma0Saikat Pramanik1Samik Bindu2Somnath Mazumder3Troyee Das4Uttam Pal5Debanjan Saha6Rudranil De7Shiladitya Nag8Chinmoy Banerjee9Nakul Chandra Maiti10Zhumur Ghosh11Uday Bandyopadhyay12Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, IndiaDivision of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, IndiaDepartment of Zoology, Cooch Behar Panchanan Barma University, Cooch Behar, West Bengal 736101, IndiaDepartment of Zoology, Raja Peary Mohan College, 1 Acharya Dhruba Pal Road, Uttarpara, West Bengal 712258, IndiaDivision of Bioinformatics, Bose Institute, EN 80, Sector V, Bidhan Nagar, Kolkata 700091, IndiaStructural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, IndiaDivision of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, IndiaAmity Institute of Biotechnology, Amity University, Kolkata, Plot No: 36, 37 & 38, Major Arterial Road, Action Area II, Kadampukur Village, Newtown, Kolkata 700135, IndiaDivision of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, IndiaDivision of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, IndiaStructural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, IndiaDivision of Bioinformatics, Bose Institute, EN 80, Sector V, Bidhan Nagar, Kolkata 700091, IndiaDivision of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India; Department of Biological Sciences, Bose Institute, Unified Academic Campus, EN 80, Sector V, Bidhan Nagar, Kolkata 700091, West Bengal, India; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004224006059Cell biologyCancer |
| spellingShingle | 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 NSAID targets SIRT3 to trigger mitochondrial dysfunction and gastric cancer cell death iScience Cell biology Cancer |
| title | NSAID targets SIRT3 to trigger mitochondrial dysfunction and gastric cancer cell death |
| title_full | NSAID targets SIRT3 to trigger mitochondrial dysfunction and gastric cancer cell death |
| title_fullStr | NSAID targets SIRT3 to trigger mitochondrial dysfunction and gastric cancer cell death |
| title_full_unstemmed | NSAID targets SIRT3 to trigger mitochondrial dysfunction and gastric cancer cell death |
| title_short | NSAID targets SIRT3 to trigger mitochondrial dysfunction and gastric cancer cell death |
| title_sort | nsaid targets sirt3 to trigger mitochondrial dysfunction and gastric cancer cell death |
| topic | Cell biology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224006059 |
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