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Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth.

Chen J, Chung F, Yang G, Pu M, Gao H, Jiang W, Yin H, Capka V, Kasibhatla S, Laffitte B, Jaeger S, Pagliarini R, Chen Y, Zhou W - Oncotarget (2013)

Bottom Line: Cancer cells rely on aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect.PHGDH knockdown in these cells leads to a reduction of serine synthesis and impairment of cancer cell proliferation.However, PHGDH knockdown does not affect tumor maintenance and growth in established breast cancer xenograft models, suggesting that PHGDH-dependent cancer cell growth may be context-dependent.

View Article: PubMed Central - PubMed

Affiliation: Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States.

ABSTRACT
Cancer cells rely on aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect. Phosphoglycerate dehydrogenase (PHDGH) catalyzes the first step of the serine biosynthetic pathway downstream of glycolysis, which is a metabolic gatekeeper both for macromolecular biosynthesis and serine-dependent DNA synthesis. Here, we report that PHDGH is overexpressed in many ER-negative human breast cancer cell lines. PHGDH knockdown in these cells leads to a reduction of serine synthesis and impairment of cancer cell proliferation. However, PHGDH knockdown does not affect tumor maintenance and growth in established breast cancer xenograft models, suggesting that PHGDH-dependent cancer cell growth may be context-dependent. Our findings suggest that other mechanisms or pathways may bypass exclusive dependence on PHGDH in established human breast cancer xenografts, indicating that PHGDH is dispensable for the growth and maintenance and of tumors in vivo.

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PHGDH shows a differential expression pattern among human breast cancer cell lines
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Figure 1: PHGDH shows a differential expression pattern among human breast cancer cell lines

Mentions: The Warburg effect is defined as aerobic glycolysis and used by cancer cells to maintain cell growth and proliferation[1]. Increased rates of glucose uptake, with a decrease in oxidative phosphorylation even in the presence of oxygen, are often observed in many types of cancer cells [1, 2]. PHGDH encodes 3-phosphoglycerate dehydrogenase, which is the first enzyme branching from glycolysis into the serine synthetic pathway (Fig.1A) [3]. It requires nicotinamide adenine dinucleotide (NAD) as a cofactor to oxidize the glycolytic intermediate 3-phosphoglycerate into phospho-hydroxypyruvate [4, 5]. The serine production pathway also includes two subsequent enzymes: phosphoserine aminotransferase 1 (PSAT1) and phosphate ester hydrolysis (PSPH) (Fig. 1A) [3]. Serine is needed for synthesis of proteins and other biomolecules in cell proliferation and its biosynthetic activity was shown to be elevated in tumor lysates [6, 7].


Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth.

Chen J, Chung F, Yang G, Pu M, Gao H, Jiang W, Yin H, Capka V, Kasibhatla S, Laffitte B, Jaeger S, Pagliarini R, Chen Y, Zhou W - Oncotarget (2013)

PHGDH shows a differential expression pattern among human breast cancer cell lines
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926844&req=5

Figure 1: PHGDH shows a differential expression pattern among human breast cancer cell lines
Mentions: The Warburg effect is defined as aerobic glycolysis and used by cancer cells to maintain cell growth and proliferation[1]. Increased rates of glucose uptake, with a decrease in oxidative phosphorylation even in the presence of oxygen, are often observed in many types of cancer cells [1, 2]. PHGDH encodes 3-phosphoglycerate dehydrogenase, which is the first enzyme branching from glycolysis into the serine synthetic pathway (Fig.1A) [3]. It requires nicotinamide adenine dinucleotide (NAD) as a cofactor to oxidize the glycolytic intermediate 3-phosphoglycerate into phospho-hydroxypyruvate [4, 5]. The serine production pathway also includes two subsequent enzymes: phosphoserine aminotransferase 1 (PSAT1) and phosphate ester hydrolysis (PSPH) (Fig. 1A) [3]. Serine is needed for synthesis of proteins and other biomolecules in cell proliferation and its biosynthetic activity was shown to be elevated in tumor lysates [6, 7].

Bottom Line: Cancer cells rely on aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect.PHGDH knockdown in these cells leads to a reduction of serine synthesis and impairment of cancer cell proliferation.However, PHGDH knockdown does not affect tumor maintenance and growth in established breast cancer xenograft models, suggesting that PHGDH-dependent cancer cell growth may be context-dependent.

View Article: PubMed Central - PubMed

Affiliation: Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States.

ABSTRACT
Cancer cells rely on aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect. Phosphoglycerate dehydrogenase (PHDGH) catalyzes the first step of the serine biosynthetic pathway downstream of glycolysis, which is a metabolic gatekeeper both for macromolecular biosynthesis and serine-dependent DNA synthesis. Here, we report that PHDGH is overexpressed in many ER-negative human breast cancer cell lines. PHGDH knockdown in these cells leads to a reduction of serine synthesis and impairment of cancer cell proliferation. However, PHGDH knockdown does not affect tumor maintenance and growth in established breast cancer xenograft models, suggesting that PHGDH-dependent cancer cell growth may be context-dependent. Our findings suggest that other mechanisms or pathways may bypass exclusive dependence on PHGDH in established human breast cancer xenografts, indicating that PHGDH is dispensable for the growth and maintenance and of tumors in vivo.

Show MeSH
Related in: MedlinePlus