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

Cui Y, Qin L, Wu J, Qu X, Hou C, Sun W, Li S, Vaughan AT, Li JJ, Liu J - PLoS ONE (2015)

Bottom Line: 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.Further analysis revealed that SIRT3 interacted with and deacetylated the lactate dehydrogenase A (LDHA), a key protein in regulating anaerobic glycolysis, enhancing LDHA activity.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Life Science, Xi'an Jiaotong University, Xi'an, 710049, China.

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.

No MeSH data available.


Related in: MedlinePlus

SIRT3 expression is associated with cellular bioenergetics.A and B, total cellular ATP levels were tested in AGS (A) and SGC-7901 (B) cells with SIRT3 overexpression or knockdown. C and D, AGS (C) and SGC-7901 (D) cells with SIRT3 overexpression or knockdown were treated with rotenone (2 μM, 24 hours) to inhibit the oxidative phosphorylation and then cytoplasm ATP levels were measured. Data were normalized by control (NC or Scr) cells and presented as mean ± S.E. (n = 3; *, p < 0.05; **, p < 0.01).
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pone.0129834.g004: SIRT3 expression is associated with cellular bioenergetics.A and B, total cellular ATP levels were tested in AGS (A) and SGC-7901 (B) cells with SIRT3 overexpression or knockdown. C and D, AGS (C) and SGC-7901 (D) cells with SIRT3 overexpression or knockdown were treated with rotenone (2 μM, 24 hours) to inhibit the oxidative phosphorylation and then cytoplasm ATP levels were measured. Data were normalized by control (NC or Scr) cells and presented as mean ± S.E. (n = 3; *, p < 0.05; **, p < 0.01).

Mentions: SIRT3 has been proven involved in the deacetylation of global metabolism enzymes and maintenance of basal ATP levels in cells both in normal condition and in diseases [1,2]. Total cellular ATP and glycolysis ATP generation were detected in AGS and SGC-7901 cells with either SIRT3 overexpression or SIRT3 knockdown. The total cellular ATP levels were increased in SIRT3 overexpressing cells (around 1.3-fold in both cell lines), but decreased in SIRT3 knockdown cells (around 75% in both cell lines) compared to NC or Scr control cells (Fig 4A and 4B). Then we treated cells with rotenone to inhibit oxidative phosphorylation, and tested ATP generation from glycolysis. As is shown in Fig 4C and 4D, SIRT3 overexpression led to an increase in glycolysis ATP production (1.4-fold in AGS and 1.6-fold in SGC-7901), while SIRT3 knockdown led to a significant decrease in glycolysis ATP production (20% in AGS and 40% in SGC-7901) compared to NC or Scr control.


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

Cui Y, Qin L, Wu J, Qu X, Hou C, Sun W, Li S, Vaughan AT, Li JJ, Liu J - PLoS ONE (2015)

SIRT3 expression is associated with cellular bioenergetics.A and B, total cellular ATP levels were tested in AGS (A) and SGC-7901 (B) cells with SIRT3 overexpression or knockdown. C and D, AGS (C) and SGC-7901 (D) cells with SIRT3 overexpression or knockdown were treated with rotenone (2 μM, 24 hours) to inhibit the oxidative phosphorylation and then cytoplasm ATP levels were measured. Data were normalized by control (NC or Scr) cells and presented as mean ± S.E. (n = 3; *, p < 0.05; **, p < 0.01).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4487898&req=5

pone.0129834.g004: SIRT3 expression is associated with cellular bioenergetics.A and B, total cellular ATP levels were tested in AGS (A) and SGC-7901 (B) cells with SIRT3 overexpression or knockdown. C and D, AGS (C) and SGC-7901 (D) cells with SIRT3 overexpression or knockdown were treated with rotenone (2 μM, 24 hours) to inhibit the oxidative phosphorylation and then cytoplasm ATP levels were measured. Data were normalized by control (NC or Scr) cells and presented as mean ± S.E. (n = 3; *, p < 0.05; **, p < 0.01).
Mentions: SIRT3 has been proven involved in the deacetylation of global metabolism enzymes and maintenance of basal ATP levels in cells both in normal condition and in diseases [1,2]. Total cellular ATP and glycolysis ATP generation were detected in AGS and SGC-7901 cells with either SIRT3 overexpression or SIRT3 knockdown. The total cellular ATP levels were increased in SIRT3 overexpressing cells (around 1.3-fold in both cell lines), but decreased in SIRT3 knockdown cells (around 75% in both cell lines) compared to NC or Scr control cells (Fig 4A and 4B). Then we treated cells with rotenone to inhibit oxidative phosphorylation, and tested ATP generation from glycolysis. As is shown in Fig 4C and 4D, SIRT3 overexpression led to an increase in glycolysis ATP production (1.4-fold in AGS and 1.6-fold in SGC-7901), while SIRT3 knockdown led to a significant decrease in glycolysis ATP production (20% in AGS and 40% in SGC-7901) compared to NC or Scr control.

Bottom Line: 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.Further analysis revealed that SIRT3 interacted with and deacetylated the lactate dehydrogenase A (LDHA), a key protein in regulating anaerobic glycolysis, enhancing LDHA activity.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Life Science, Xi'an Jiaotong University, Xi'an, 710049, China.

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.

No MeSH data available.


Related in: MedlinePlus