SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis
Abstract Cholangiocarcinoma (CCA) is an extremely invasive malignancy with late diagnosis and unfavorable prognosis. Surgery and chemotherapy are still not effective in improving outcomes in CCA patients. It is crucial to explore a novel therapeutic target for treating CCA. An NAD‐dependent deacetyl...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-05-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.2089 |
| _version_ | 1797236902357630976 |
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| author | Lei Xu Yang Li Lixing Zhou Robert Gregory Dorfman Li Liu Rui Cai Chenfei Jiang Dehua Tang Yuming Wang Xiaoping Zou Lei Wang Mingming Zhang |
| author_facet | Lei Xu Yang Li Lixing Zhou Robert Gregory Dorfman Li Liu Rui Cai Chenfei Jiang Dehua Tang Yuming Wang Xiaoping Zou Lei Wang Mingming Zhang |
| author_sort | Lei Xu |
| collection | DOAJ |
| description | Abstract Cholangiocarcinoma (CCA) is an extremely invasive malignancy with late diagnosis and unfavorable prognosis. Surgery and chemotherapy are still not effective in improving outcomes in CCA patients. It is crucial to explore a novel therapeutic target for treating CCA. An NAD‐dependent deacetylase also known as Sirtuin‐3 (SIRT3) has been shown to regulate cellular metabolism in various cancers dynamically. However, the biological function of SIRT3 in CCA remains unclear. In this study, bioinformatics analyses were performed to identify the differentially expressed genes and pathways enriched. CCA samples were collected for immunohistochemical analysis. Three human CCA cell lines (HuCCT1, RBE, and HCCC9810) were used to explore the molecular mechanism of SIRT3 regulation of metabolic reprogramming and malignant behavior in CCA. A CCA xenograft model was then established for further validation in vivo. The data showed that SIRT3 expression was decreased and glycolysis was enhanced in CCA. Similar metabolic reprogramming was also observed in SIRT3 knockout mice. Furthermore, we demonstrated that SIRT3 could play an anti‐Warburg effect by inhibiting the hypoxia‐inducible factor‐1α (HIF1α)/pyruvate dehydrogenase kinase 1 (PDK1)/pyruvate dehydrogenase (PDHA1) pathway in CCA cells. CCA cell proliferation and apoptosis were regulated by SIRT3‐mediated metabolic reprogramming. These findings were further confirmed in CCA clinical samples and the xenograft model. Collectively, this study suggests that in the inhibition of CCA progression, SIRT3 acts through an anti‐Warburg effect on the downstream pathway HIF1α/PDK1/PDHA1. |
| first_indexed | 2024-04-24T17:11:14Z |
| format | Article |
| id | doaj.art-0655b35ca1504e9dbac554b3c9d42748 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-04-24T17:11:14Z |
| publishDate | 2019-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-0655b35ca1504e9dbac554b3c9d427482024-03-28T10:30:36ZengWileyCancer Medicine2045-76342019-05-01852380239110.1002/cam4.2089SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesisLei Xu0Yang Li1Lixing Zhou2Robert Gregory Dorfman3Li Liu4Rui Cai5Chenfei Jiang6Dehua Tang7Yuming Wang8Xiaoping Zou9Lei Wang10Mingming Zhang11Department of Gastroenterology Drum Tower Clinical Medical College of Nanjing Medical University Nanjing ChinaDepartment of Gastroenterology First Affiliated Hospital of Anhui Medical University Hefei ChinaThe Center of Gerontology and Geriatrics West China Hospital, Sichuan University Chengdu ChinaFeinberg School of Medicine Northwestern University Chicago ILDepartment of Gastroenterology Drum Tower Clinical Medical College of Nanjing Medical University Nanjing ChinaDepartment of Gastroenterology Drum Tower Clinical Medical College of Nanjing Medical University Nanjing ChinaDepartment of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School Nanjing University Nanjing ChinaDepartment of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School Nanjing University Nanjing ChinaDepartment of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School Nanjing University Nanjing ChinaDepartment of Gastroenterology Drum Tower Clinical Medical College of Nanjing Medical University Nanjing ChinaDepartment of Gastroenterology Drum Tower Clinical Medical College of Nanjing Medical University Nanjing ChinaDepartment of Gastroenterology Drum Tower Clinical Medical College of Nanjing Medical University Nanjing ChinaAbstract Cholangiocarcinoma (CCA) is an extremely invasive malignancy with late diagnosis and unfavorable prognosis. Surgery and chemotherapy are still not effective in improving outcomes in CCA patients. It is crucial to explore a novel therapeutic target for treating CCA. An NAD‐dependent deacetylase also known as Sirtuin‐3 (SIRT3) has been shown to regulate cellular metabolism in various cancers dynamically. However, the biological function of SIRT3 in CCA remains unclear. In this study, bioinformatics analyses were performed to identify the differentially expressed genes and pathways enriched. CCA samples were collected for immunohistochemical analysis. Three human CCA cell lines (HuCCT1, RBE, and HCCC9810) were used to explore the molecular mechanism of SIRT3 regulation of metabolic reprogramming and malignant behavior in CCA. A CCA xenograft model was then established for further validation in vivo. The data showed that SIRT3 expression was decreased and glycolysis was enhanced in CCA. Similar metabolic reprogramming was also observed in SIRT3 knockout mice. Furthermore, we demonstrated that SIRT3 could play an anti‐Warburg effect by inhibiting the hypoxia‐inducible factor‐1α (HIF1α)/pyruvate dehydrogenase kinase 1 (PDK1)/pyruvate dehydrogenase (PDHA1) pathway in CCA cells. CCA cell proliferation and apoptosis were regulated by SIRT3‐mediated metabolic reprogramming. These findings were further confirmed in CCA clinical samples and the xenograft model. Collectively, this study suggests that in the inhibition of CCA progression, SIRT3 acts through an anti‐Warburg effect on the downstream pathway HIF1α/PDK1/PDHA1.https://doi.org/10.1002/cam4.2089CholangiocarcinomaMetabolic reprogrammingSIRT3Warburg effect |
| spellingShingle | Lei Xu Yang Li Lixing Zhou Robert Gregory Dorfman Li Liu Rui Cai Chenfei Jiang Dehua Tang Yuming Wang Xiaoping Zou Lei Wang Mingming Zhang SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis Cancer Medicine Cholangiocarcinoma Metabolic reprogramming SIRT3 Warburg effect |
| title | SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis |
| title_full | SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis |
| title_fullStr | SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis |
| title_full_unstemmed | SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis |
| title_short | SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis |
| title_sort | sirt3 elicited an anti warburg effect through hif1α pdk1 pdha1 to inhibit cholangiocarcinoma tumorigenesis |
| topic | Cholangiocarcinoma Metabolic reprogramming SIRT3 Warburg effect |
| url | https://doi.org/10.1002/cam4.2089 |
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