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Cancer Med. 2019 May;8(5):2380-2391. doi: 10.1002/cam4.2089. Epub 2019 Apr 16.

SIRT3 elicited an anti-Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis.

Author information

1
Department of Gastroenterology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, China.
2
Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, China.
3
Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China.
4
The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
5
Feinberg School of Medicine, Northwestern University, Chicago, IL.

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.

KEYWORDS:

Cholangiocarcinoma; Metabolic reprogramming; SIRT3; Warburg effect

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