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SIRT3 Enhances Glycolysis and Proliferation in SIRT3-Expressing Gastric Cancer Cells.

ABSTRACT: SIRT3 is a key NAD+-dependent protein deacetylase in the mitochondria of mammalian cells, functioning to prevent cell aging and transformation via regulation of mitochondrial metabolic homeostasis. However, SIRT3 is also found to express in some human tumors; its role in these SIRT3-expressing tumor cells needs to be elucidated. This study demonstrated that the expression of SIRT3 was elevated in a group of gastric cancer cells compared to normal gastric epithelial cells. Although SIRT3 expression levels were increased in the gastric tumor tissues compared to the adjacent non-tumor tissues, SIRT3 positive cancer cells were more frequently detected in the intestinal type gastric cancers than the diffuse type gastric cancers, indicating that SIRT3 is linked with subtypes of gastric cancer. Overexpression of SIRT3 promoted cell proliferation and enhanced ATP generation, glucose uptake, glycogen formation, MnSOD activity and lactate production, which were inhibited by SIRT3 knockdown, indicating that SIRT3 plays a role in reprogramming the bioenergetics in gastric tumor cells. Further analysis revealed that SIRT3 interacted with and deacetylated the lactate dehydrogenase A (LDHA), a key protein in regulating anaerobic glycolysis, enhancing LDHA activity. In consistence, a cluster of glycolysis-associated genes was upregulated in the SIRT3-overexpressing gastric tumor cells. Thus, in addition to the well-documented SIRT3-mediated mitochondrial homeostasis in normal cells, SIRT3 may enhance glycolysis and cell proliferation in SIRT3-expressing cancer cells.

SUBMITTER: Cui Y

PROVIDER: S-EPMC4487898 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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SIRT3 Enhances Glycolysis and Proliferation in SIRT3-Expressing Gastric Cancer Cells.

Cui Yang Y Qin Lili L Wu Jing J Qu Xuan X Hou Chen C Sun Wenyan W Li Shiyong S Vaughan Andrew T M AT Li Jian Jian JJ Liu Jiankang J

PloS one 20150629 6

SIRT3 is a key NAD+-dependent protein deacetylase in the mitochondria of mammalian cells, functioning to prevent cell aging and transformation via regulation of mitochondrial metabolic homeostasis. However, SIRT3 is also found to express in some human tumors; its role in these SIRT3-expressing tumor cells needs to be elucidated. This study demonstrated that the expression of SIRT3 was elevated in a group of gastric cancer cells compared to normal gastric epithelial cells. Although SIRT3 expressi ...[more]

PMID: 26121691

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Project description:BACKGROUND:The study aims to present the effect of PIK3CA E542K and E545K mutations on glucose metabolism and proliferation and identify their underlying mechanisms in cervical cancer. METHODS:The maximum standard uptake value (SUVmax) of tumors was detected by18F-FDG PET/CT scan. In vitro, glycolysis analysis, extracellular acidification rate analysis, and ATP production were used to evaluate the impact of PIK3CA E542K and E545K mutations on glucose metabolism. The expression level of key glycolytic enzymes was evaluated by western blotting and immunohistochemical staining in cervical cancer cells and tumor tissues, respectively. Immunofluorescence analysis was used to observe the nuclear translocation of ?-catenin. The target gene of ?-catenin was analyzed by using luciferase reporter system. The glucose metabolic ability of the xenograft models was assessed by SUVmax from microPET/CT scanning. RESULTS:Cervical cancer patients with mutant PIK3CA (E542K and E545K) exhibited a higher SUVmax value than those with wild-type PIK3CA (P =?0.037), which was confirmed in xenograft models. In vitro, enhanced glucose metabolism and proliferation was observed in SiHa and MS751 cells with mutant PIK3CA. The mRNA and protein expression of key glycolytic enzymes was increased. AKT/GSK3?/?-catenin signaling was highly activated in SiHa and MS751 cells with mutant PIK3CA. Knocking down ?-catenin expression decreased glucose uptake and lactate production. In addition, the nuclear accumulation of ?-catenin was found in SiHa cells and tumors with mutant PIK3CA. Furthermore, ?-catenin downregulated the expression of SIRT3 via suppressing the activity of the SIRT3 promotor, and the reduced glucose uptake and lactate production due to the downregulation of ?-catenin can be reversed by the transfection of SIRT3 siRNA in SiHa cells with mutant PIK3CA. The negative correlation between ?-catenin and SIRT3 was further confirmed in cervical cancer tissues. CONCLUSIONS:These findings provide evidence that the PI3K E542K and E545K/?-catenin/SIRT3 signaling axis regulates glucose metabolism and proliferation in cervical cancers with PIK3CA mutations, suggesting therapeutic targets in the treatment of cervical cancers. TRIAL REGISTRATION:FUSCC 050432-4-1212B. Registered 24 December 2012 (retrospectively registered).

Dataset Information

SIRT3 Enhances Glycolysis and Proliferation in SIRT3-Expressing Gastric Cancer Cells.

Publications

SIRT3 Enhances Glycolysis and Proliferation in SIRT3-Expressing Gastric Cancer Cells.

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