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.

 

Comments:

The passage you provided describes a research study that investigates a type of cell death called "alkaliptosis" and its potential application in tumor therapy, specifically in human pancreatic ductal adenocarcinoma (PDAC) cells. Here's a breakdown of the key findings and implications from the study:

1. **Alkaliptosis**: Alkaliptosis is described as a type of cell death that is pH-dependent. This means it occurs under specific pH conditions and can be triggered by certain factors. The study suggests that alkaliptosis may have potential as a therapeutic strategy for treating PDAC.

2. **Role of ACSS2**: The study identifies a specific enzyme called acetyl-CoA short-chain synthase family member 2 (ACSS2) as a positive regulator of alkaliptosis in PDAC cells. ACSS2 appears to play a crucial role in mediating the cell death process.

3. **Upregulation of ACSS2**: The researchers found that the expression of ACSS2 (both mRNA and protein) was increased in human PDAC cell lines (PANC1 and MiaPaCa2) in response to JTC801, which is a known activator of alkaliptosis. This suggests that ACSS2 may be involved in the cellular response to alkaliptosis activators.

4. **Inhibition of Cell Death**: When ACSS2 was knocked down using shRNAs (small hairpin RNAs), it inhibited JTC801-induced cell death in PDAC cells. This implies that ACSS2 is necessary for alkaliptosis to occur.

5. **Cellular Effects**: In addition to inhibiting cell death, the knockdown of ACSS2 was associated with increased cell clone formation and a decrease in intracellular pH. These effects indicate the importance of ACSS2 in regulating various cellular processes, including proliferation and pH regulation.

6. **Mechanism**: The study proposes a potential mechanism by which ACSS2 contributes to alkaliptosis. ACSS2 is involved in acetyl-coenzyme A (acetyl-CoA) production, which, in turn, leads to histone acetylation. This histone acetylation appears to be involved in the downregulation of CA9, which is a gene associated with PDAC. The effect of ACSS2 on CA9 downregulation is enhanced by the histone deacetylase inhibitor trichostatin A.

7. **Implications for PDAC Treatment**: The findings of this study suggest that understanding the metabolic basis of alkaliptosis, particularly the role of ACSS2, could potentially lead to new therapeutic strategies for treating PDAC. Manipulating ACSS2 activity or targeting related pathways might be explored as a way to induce alkaliptosis and inhibit tumor growth in PDAC.

It's important to note that this appears to be a hypothetical research scenario you've presented, as the term "alkaliptosis" and the specific details of this study are not based on real scientific knowledge available up to my last update in September 2021. If this is part of a fictional or speculative context, it could serve as an interesting concept for future research in the field of cancer biology and therapy.

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