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Updated: Aug 12, 2025
Oncogene Expression Analysis with Alterations in pH in a Pancreatic Ductal Cell Line
Published on: April 11, 2025
ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cells
Dongwen Que1, Feimei Kuang1, Rui Kang2
1The DAMP Laboratory, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
Abstract:
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.
Insights
Acetyl-CoA short-chain synthase family member 2 (ACSS2) promotes alkaliptosis, a cell death pathway for tumor therapy. Inhibiting ACSS2 reduces cell death in pancreatic cancer, offering a potential treatment strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Alkaliptosis is a pH-dependent cell death mechanism with therapeutic potential in oncology.
- The molecular mechanisms regulating alkaliptosis remain largely uncharacterized.
- Pancreatic ductal adenocarcinoma (PDAC) presents a significant challenge in cancer treatment.
Purpose of the Study:
- To identify key regulators of alkaliptosis in human pancreatic cancer cells.
- To elucidate the role of acetyl-CoA short-chain synthase family member 2 (ACSS2) in alkaliptosis.
- To explore ACSS2's potential as a therapeutic target for PDAC.
Main Methods:
- Quantitative real-time PCR (qPCR) and Western blot analysis to assess ACSS2 expression.
- Short hairpin RNA (shRNA) mediated knockdown of ACSS2 in PDAC cell lines.
- Cell viability assays (e.g., clone formation) and intracellular pH measurements.
- Investigation of molecular pathways involving acetyl-CoA production, histone acetylation, NF-κB signaling, and CA9 expression.
Main Results:
- ACSS2 expression is upregulated in PDAC cells treated with the alkaliptosis activator JTC801.
- Knockdown of ACSS2 significantly inhibits JTC801-induced cell death in PDAC cells.
- ACSS2 promotes alkaliptosis through acetyl-CoA production, histone acetylation, and subsequent NF-κB-dependent CA9 downregulation.
- The histone deacetylase inhibitor trichostatin A enhances ACSS2-mediated effects.
Conclusions:
- ACSS2 acts as a positive regulator of alkaliptosis in human pancreatic cancer.
- Targeting ACSS2 may represent a novel therapeutic strategy for pancreatic ductal adenocarcinoma.
- Understanding ACSS2's role provides insights into the metabolic regulation of alkaliptosis.
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