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Sirtuin 3 is a common target of non-steroidal anti-inflammatory drugs to induce gastric cancer cell death and gastric mucosal injury.

ABSTRACT: Nonsteroidal anti-inflammatory drugs (NSAIDs), the quintessential medicines to treat pain and inflammatory conditions, induce cell death in human cancer cells, as repurposed anticancer agents, and in normal gastric mucosa, as a major side effect. The subcellular target/s of NSAIDs that leads to the cell death remained elusive so far. Here, by venturing transcriptomics followed by functional validation, we, for the first time, identified mitochondrial deacetylase Sirtuin 3 (Sirt3) as a non-canonical target of NSAIDs whose depletion induced the hyperacetylation of mitochondrial proteome, OGG1 depletion, mtDNA damage, electron transport chain defect associated mitochondrial dysfunction and finally cell death. Silencing of Sirt3 in AGS cells (a human gastric adenocarcinoma cell line) significantly aggravated NSAID-induced cytopathology. Whereas, honokiol mediated induction of Sirt3 corrected the NSAID-induced transcriptome alteration and gastropathy in rodent model. Together, the results identify Sirt3 as a common target used by NSAIDs to induce gastric carcinoma cell death and gastric mucosal injury.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE201565 | GEO | 2022/11/14

REPOSITORIES: GEO

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Project description:Acute myeloid leukemia is a heterogeneous disease with regard to the underlying genetic and molecular pathophysiology. Non-steroidal anti-inflammatory drugs (NSAIDs) exert significant anti-proliferative effects in various malignant cells in vitro and in vivo. Hence, these agents can be utilized to study potential disease specific anti-proliferative pathways. In this study, a total number of 42 bone marrow derived CD34+ cells from de novo AML patients and the AML cell lines THP-1 and HL-60 were treated with the NSAIDs Sulindac sulfide and Diclofenac. We examined viability, apoptosis, differentiation and addressed the molecular mechanisms involved. We found a consistent induction of apoptosis and to some extent myeloid differentiation in NSAID treated AML cells. Comprehensive protein and gene expression profiling of Diclofenac treated AML cells revealed transcriptional activation of GADD45M-NM-1 and its downstream MAPK/JNK pathway as well as increased protein levels of the Caspase-3 precursor. This points towards a role of the c-Jun NH2-terminal kinase (JNK) in NSAID mediated apoptosis. This was dependent on JNK activity as addition of a specific JNK-inhibitor abrogated apoptosis. Furthermore, the AP-1 transcription factor family membersM-bM-^@M-^Y c-Jun, JunB and Fra-2 were transcriptionally activated in NSAID treated AML cells. Re-expression of these transcription factors led to activation of GADD45M-NM-1 with induction of apoptosis. Mechanistically, we demonstrate that NSAIDs induce apoptosis in AML through a novel pathway involving increased expression of AP-1 heterodimers, which by itself is sufficient to induce GADD45M-NM-1 expression with consecutive activation of JNK and induction of apoptosis. HL-60 and THP-1 AML cells were treated with 100 M-BM-5M Diclofenac or DMSO as control for 48 hours. Each experiment was performed in duplicate. After this treatment total RNA of the cells was harvested and analysed by means of gene expression profiling with the Affymetrix HU-133A array.

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Sirtuin 3 is a common target of non-steroidal anti-inflammatory drugs to induce gastric cancer cell death and gastric mucosal injury.

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