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 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.

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

“…[37] SIRT3 effects mediated by HIF1α/ PDK1/PDHA1 pathway Decrease of SIRT3 expression induced the glycolytic flux through the hypoxia inducible factor α (HIF1α)/PDK1/ PDHA1 axis, promoting CCA progression. [38] Deregulation of PI3K-AKT-mTOR signaling Protein overexpression and activation of PI3K have been associated with tumor progression, differentiation, nodal involvement and reduced OS. Upregulation of activated form of AKT have been reported in neoplastic cells compared to the surrounding normal tissue; Increased mTOR gene copy number and elevated phospho-mTOR levels have been described in biliary cancer specimens in comparison to the adjacent normal or dysplastic epithelium.…”

“…The authors showed that in CCA cells, as well as in both tissue samples and in a xenograft model, SIRT3 was downregulated and the glycolysis enhanced. Conversely, the induction of SIRT3 was able to efficiently reduce tumor proliferation via an anti-Warburg effect mediated by the HIF1α/PDK1/PDHA1 pathway [38] (Table 1).…”

Role of Glucose Metabolism Reprogramming in the Pathogenesis of Cholangiocarcinoma

“…Furthermore, the authors also confirmed that SIRT3 prevents the Warburg effect in CCA cells and a xenograft mouse model by inhibiting the HIF1α/PDK1/PDHA1 pathway. Collectively, this study suggests that SIRT3 shows anti-Warburg effect activity via regulating the HIF1α/PDK1/PDHA1 pathway and may be a potential therapeutic intervention to impair CCA progression (39).…”

Impact of Sirtuin Enzymes on the Altered Metabolic Phenotype of Malignantly Transformed Cells

“…The first reported target of SIRT3 was acetyl-CoA synthetase 2 (AceCS2) (46), that promotes metastasis formation of renal cell carcinoma (47), however, in gastric cancer, loss of AceCS2 expression predicts poor prognosis (48), which further emphasizes the significance of TME. SIRT3 downregulates HIF1α and pyruvate dehydrogenase kinase 1 (PDK1) in cholangiocarcinoma (49), and suppresses the Warburg effect also by the activation of pyruvate dehydrogenase complex (PDC) and the indirect inhibition of the tumor specific isoenzyme hexokinase II (HK II) (11). SIRT3 regulates fatty acid oxidation via the deacetylation and activation of long chain acyl-CoA dehydrogenase (LCAD) enzyme (50), opposite to HIF1α that suppresses fatty acid oxidation to facilitate cancer progression (51).…”