Sirtuin 4 Depletion Promotes Hepatocellular Carcinoma Tumorigenesis Through Regulating Adenosine‐Monophosphate–Activated Protein Kinase Alpha/Mammalian Target of Rapamycin Axis in Mice
Autor: | Peng Meng, Bo Tang, Xingsi Liang, Lutao Du, Lei Bi, Yuli Wang, Chuanxin Wang, Yunshan Wang |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Adenosine monophosphate Carcinoma Hepatocellular Carcinogenesis Glutamine Down-Regulation AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Mitochondrial Proteins 03 medical and health sciences chemistry.chemical_compound Liver Neoplasms Experimental 0302 clinical medicine Animals Humans Sirtuins Protein kinase A PI3K/AKT/mTOR pathway Mice Knockout Sirolimus Glutaminolysis Hepatology Kinase TOR Serine-Threonine Kinases Hep G2 Cells HCCS Adenosine Monophosphate digestive system diseases 030104 developmental biology chemistry Cancer research 030211 gastroenterology & hepatology Signal transduction Adenosine triphosphate Signal Transduction |
Zdroj: | Hepatology. 69:1614-1631 |
ISSN: | 1527-3350 0270-9139 |
Popis: | Sirtuin 4 (SIRT4) has been reported to play a vital role in the maintenance of glutamine catabolism and adenosine triphosphate (ATP) homeostasis, but its character in hepatocellular carcinomas (HCCs) remains obscure. In this study, we observed low expression of SIRT4 in both HCC cell lines and HCCs from patients. Decreased disease-free survival time is associated with low tumor levels of SIRT4 in patients. Deficiency of SIRT4 facilitated liver tumor development and lung metastasis in xenografts and knockout (KO) mice by promoting colony formation and migration of hepatoma cells and enhancing sphere formation of HCCs. Mechanistically, SIRT4 deletion augmented mammalian target of rapamycin (mTOR) signaling by inactivating adenosine-monophosphate (AMP)-activated protein kinase alpha (AMPKα) through regulation of glutamine catabolism and subsequent AM)/liver kinase B1 (LKB1) axis. Blockage of mTOR by rapamycin or inhibition of glutaminolysis abolished the discrepancy in tumorigenic capacity between SIRT4-depleted hepatoma cells and control cells. Suppression of LKB1 or promotion of AMP by metformin also abrogated the hyperproliferative phenotype caused by SIRT4 loss, which further confirmed that the LKB1/AMPKα/mTOR axis is required in SIRT4-deficiency-promoted HCC tumorigenesis. Conclusion: SIRT4 could exert its tumor suppressive function in HCC by inhibiting glutamine metabolism and thereby increasing the adenosine diphosphate (ADP)/AMP levels to phosphorylate AMPKα by LKB1, which blocks the mTOR signaling pathway. |
Databáze: | OpenAIRE |
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