ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cells
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)...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-28261-4 |
| _version_ | 1811175794136842240 |
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| author | Dongwen Que Feimei Kuang Rui Kang Daolin Tang Jiao Liu |
| author_facet | Dongwen Que Feimei Kuang Rui Kang Daolin Tang Jiao Liu |
| author_sort | Dongwen Que |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T19:42:47Z |
| format | Article |
| id | doaj.art-2411754a82c148c691fdabbb86a40bf2 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-10T19:42:47Z |
| publishDate | 2023-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-2411754a82c148c691fdabbb86a40bf22023-01-29T12:12:54ZengNature PortfolioScientific Reports2045-23222023-01-0113111010.1038/s41598-023-28261-4ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cellsDongwen Que0Feimei Kuang1Rui Kang2Daolin Tang3Jiao Liu4The DAMP Laboratory, Third Affiliated Hospital of Guangzhou Medical UniversityThe DAMP Laboratory, Third Affiliated Hospital of Guangzhou Medical UniversityDepartment of Surgery, UT Southwestern Medical CenterDepartment of Surgery, UT Southwestern Medical CenterThe DAMP Laboratory, Third Affiliated Hospital of Guangzhou Medical UniversityAbstract 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.https://doi.org/10.1038/s41598-023-28261-4 |
| spellingShingle | Dongwen Que Feimei Kuang Rui Kang Daolin Tang Jiao Liu ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cells Scientific Reports |
| title | ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cells |
| title_full | ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cells |
| title_fullStr | ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cells |
| title_full_unstemmed | ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cells |
| title_short | ACSS2-mediated NF-κB activation promotes alkaliptosis in human pancreatic cancer cells |
| title_sort | acss2 mediated nf κb activation promotes alkaliptosis in human pancreatic cancer cells |
| url | https://doi.org/10.1038/s41598-023-28261-4 |
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