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ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cells

Alkaliptosis is a recently discovered type of pH-dependent cell death used for tumor therapy. However, its underlying molecular mechanisms and regulatory networks are largely unknown. Here, we report that the acetate-activating enzyme acetyl-CoA short-chain synthase family member 2 (ACSS2) is a positive regulator of alkaliptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Using qPCR and western blot analysis, we found that the mRNA and protein expression of ACSS2 was upregulated in human PDAC cell lines (PANC1 and MiaPaCa2) in response to the classic alkaliptosis activator JTC801. Consequently, the knockdown of ACSS2 by shRNAs inhibited JTC801-induced cell death in PDAC cells, and was accompanied by an increase in cell clone formation and a decrease in intracellular pH. Mechanically, ACSS2-mediated acetyl-coenzyme A production and subsequent histone acetylation contributed to NF-κB-dependent CA9 downregulation, and this effect was enhanced by the histone deacetylase inhibitor trichostatin A. These findings may provide new insights for understanding the metabolic basis of alkaliptosis and establish a potential strategy for PDAC treatment.

 

 

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The passage you provided discusses a study on a recently discovered form of cell death called alkaliptosis, which has potential applications in tumor therapy, particularly for human pancreatic ductal adenocarcinoma (PDAC) cells. The study focuses on the role of the enzyme ACSS2 (acetyl-CoA short-chain synthase family member 2) as a positive regulator of alkaliptosis in PDAC cells.

The researchers observed that the expression of ACSS2, both at the mRNA and protein levels, was increased in human PDAC cell lines (PANC1 and MiaPaCa2) when exposed to JTC801, a known activator of alkaliptosis. The knockdown of ACSS2 using shRNAs (short hairpin RNAs) reduced the JTC801-induced cell death in PDAC cells. Additionally, ACSS2 knockdown resulted in increased cell clone formation and a decrease in intracellular pH.

The study investigated the underlying molecular mechanisms by which ACSS2 regulates alkaliptosis. The researchers found that ACSS2-mediated production of acetyl-coenzyme A and subsequent histone acetylation played a role in the downregulation of CA9 (carbonic anhydrase 9), a protein involved in pH regulation. This effect was further enhanced by the histone deacetylase inhibitor trichostatin A. The downregulation of CA9 was found to be mediated through the NF-κB pathway.

These findings provide new insights into the metabolic basis of alkaliptosis and suggest that targeting ACSS2 and histone acetylation could be a potential strategy for the treatment of PDAC. Further research is needed to fully understand the regulatory networks and molecular mechanisms involved in alkaliptosis and its therapeutic implications.

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S8588 ACSS2 inhibitor ACSS2 inhibitor is the most potent and specific inhibitor of acetate-dependent acetyl-CoA synthetase 2 (ACSS2). ACSS2 inhibitor also inhibits the respiratory syncytial virus (RSV).

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RSV ACSS2