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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

Enhanced SIRT3 expression in human gastric cancer cell lines and tumor tissues.A, SIRT3 protein levels were determined by western blot in 4 gastric cancer cell lines and an immortalized normal gastric epithelium cell line GES-1 (upper panel). SIRT3 protein expression tested in three separate western blots was estimated by measuring the band intensity using Image-Pro Plus software and normalized with β-actin (lower panel). B, SIRT3 mRNA levels were detected by qRT-PCR in 4 gastric cancer cell lines. Data were normalized to immortalized normal gastric epithelium cells. In (A, B), data are presented as mean ± S.E. (n = 3; *, p < 0.05; **, p < 0.01). C, SIRT3 expression in human gastric tumor tissues (n = 29) and adjacent non-tumor tissues (n = 14) was detected by immunohistochemistry staining. SIRT3 expression levels were estimated by density scanning using Image-Pro Plus software and graded as negative, weak positive and strong positive. Scale bar, 50 μm. D, SIRT3 expression in tumor and adjacent non-tumor tissues was presented as percentage of patient specimens. E, SIRT3 expression in intestinal (n = 18) and diffuse (n = 11) types of gastric tumor tissues was presented as percentage of patient specimens.
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pone.0129834.g001: Enhanced SIRT3 expression in human gastric cancer cell lines and tumor tissues.A, SIRT3 protein levels were determined by western blot in 4 gastric cancer cell lines and an immortalized normal gastric epithelium cell line GES-1 (upper panel). SIRT3 protein expression tested in three separate western blots was estimated by measuring the band intensity using Image-Pro Plus software and normalized with β-actin (lower panel). B, SIRT3 mRNA levels were detected by qRT-PCR in 4 gastric cancer cell lines. Data were normalized to immortalized normal gastric epithelium cells. In (A, B), data are presented as mean ± S.E. (n = 3; *, p < 0.05; **, p < 0.01). C, SIRT3 expression in human gastric tumor tissues (n = 29) and adjacent non-tumor tissues (n = 14) was detected by immunohistochemistry staining. SIRT3 expression levels were estimated by density scanning using Image-Pro Plus software and graded as negative, weak positive and strong positive. Scale bar, 50 μm. D, SIRT3 expression in tumor and adjacent non-tumor tissues was presented as percentage of patient specimens. E, SIRT3 expression in intestinal (n = 18) and diffuse (n = 11) types of gastric tumor tissues was presented as percentage of patient specimens.

Mentions: SIRT3 is well-defined in regulating mitochondrial homeostasis in anti-aging and anti-transformation. Recently, different results are reported regarding to SIRT3-mediated cell inhibition and proliferation, leading to the controversy of its roles in cancers [19,20]. To determine the potential role of SIRT3 in gastric cancer, expression of SIRT3 was detected in 4 gastric cancer cell lines AGS, SGC-7901, MGC-803, HGC-27 and a group of gastric cancer tumor tissues. We found that SIRT3 protein levels were elevated in all 4 gastric cancer cell lines compared to the immortalized gastric epithelial GES-1 cells (AGS, 1.9-fold; SGC-7901, 1.5-fold; MGC-803, 2.0-fold; and HGC-27, 1.8-fold compared to GES-1 cells) (Fig 1A). In accordance, the mRNA levels of SIRT3 in these cell lines were also increased (AGS, 2.6-fold; SGC-7901, 1.7-fold; MGC-803, 2.5-fold; HGC-27, 2.2-fold) compared to GES-1 cells (Fig 1B).


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)

Enhanced SIRT3 expression in human gastric cancer cell lines and tumor tissues.A, SIRT3 protein levels were determined by western blot in 4 gastric cancer cell lines and an immortalized normal gastric epithelium cell line GES-1 (upper panel). SIRT3 protein expression tested in three separate western blots was estimated by measuring the band intensity using Image-Pro Plus software and normalized with β-actin (lower panel). B, SIRT3 mRNA levels were detected by qRT-PCR in 4 gastric cancer cell lines. Data were normalized to immortalized normal gastric epithelium cells. In (A, B), data are presented as mean ± S.E. (n = 3; *, p < 0.05; **, p < 0.01). C, SIRT3 expression in human gastric tumor tissues (n = 29) and adjacent non-tumor tissues (n = 14) was detected by immunohistochemistry staining. SIRT3 expression levels were estimated by density scanning using Image-Pro Plus software and graded as negative, weak positive and strong positive. Scale bar, 50 μm. D, SIRT3 expression in tumor and adjacent non-tumor tissues was presented as percentage of patient specimens. E, SIRT3 expression in intestinal (n = 18) and diffuse (n = 11) types of gastric tumor tissues was presented as percentage of patient specimens.
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pone.0129834.g001: Enhanced SIRT3 expression in human gastric cancer cell lines and tumor tissues.A, SIRT3 protein levels were determined by western blot in 4 gastric cancer cell lines and an immortalized normal gastric epithelium cell line GES-1 (upper panel). SIRT3 protein expression tested in three separate western blots was estimated by measuring the band intensity using Image-Pro Plus software and normalized with β-actin (lower panel). B, SIRT3 mRNA levels were detected by qRT-PCR in 4 gastric cancer cell lines. Data were normalized to immortalized normal gastric epithelium cells. In (A, B), data are presented as mean ± S.E. (n = 3; *, p < 0.05; **, p < 0.01). C, SIRT3 expression in human gastric tumor tissues (n = 29) and adjacent non-tumor tissues (n = 14) was detected by immunohistochemistry staining. SIRT3 expression levels were estimated by density scanning using Image-Pro Plus software and graded as negative, weak positive and strong positive. Scale bar, 50 μm. D, SIRT3 expression in tumor and adjacent non-tumor tissues was presented as percentage of patient specimens. E, SIRT3 expression in intestinal (n = 18) and diffuse (n = 11) types of gastric tumor tissues was presented as percentage of patient specimens.
Mentions: SIRT3 is well-defined in regulating mitochondrial homeostasis in anti-aging and anti-transformation. Recently, different results are reported regarding to SIRT3-mediated cell inhibition and proliferation, leading to the controversy of its roles in cancers [19,20]. To determine the potential role of SIRT3 in gastric cancer, expression of SIRT3 was detected in 4 gastric cancer cell lines AGS, SGC-7901, MGC-803, HGC-27 and a group of gastric cancer tumor tissues. We found that SIRT3 protein levels were elevated in all 4 gastric cancer cell lines compared to the immortalized gastric epithelial GES-1 cells (AGS, 1.9-fold; SGC-7901, 1.5-fold; MGC-803, 2.0-fold; and HGC-27, 1.8-fold compared to GES-1 cells) (Fig 1A). In accordance, the mRNA levels of SIRT3 in these cell lines were also increased (AGS, 2.6-fold; SGC-7901, 1.7-fold; MGC-803, 2.5-fold; HGC-27, 2.2-fold) compared to GES-1 cells (Fig 1B).

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