Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis

Abstract

Most tumors display increased glucose metabolism compared to that of normal tissues. The preferential conversion of glucose to lactate in cancer cells (the Warburg Effect) has been emphasized1; however, the extent to which metabolic fluxes originating from glucose are utilized for alternative processes is poorly understood2,3. Here we used a combination of mass spectrometry and NMR with stable isotope labeling to investigate the alternate pathways derived from glucose metabolism in cancer cells. We found that in some cancer cells, a relatively large amount of glycolytic carbon is diverted into serine and glycine biosynthesis through phosphoglycerate dehydrogenase (PHGDH). A bioinformatics analysis of 3131 human cancers revealed that the gene PHGDH at 1p12 is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma in which amplification was associated with increased protein expression. Decreased PHGDH expression by RNA interference impaired growth and flux into serine metabolism in PHGDH-amplified cell lines. Increased expression was also associated with breast cancer subtypes and ectopic expression of PHGDH in mammary epithelial cells (MCF-10a) disrupted acinar morphogenesis, induced loss of polarity, and preserved the viability of the extracellular matrix-deprived cells, each being phenotypic alterations that may predispose cells to transformation. Our findings demonstrate that altered metabolic flux from glucose into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.

Metabolic Pathway Alterations that Support Cell Proliferation

“…7). In support of this prediction, many cancer cells exhibit increased flux from glucose into serine and glycine biosynthesis (Locasale et al 2011). Serine and glycine are important precursors to make proteins, lipids, and nucleic acids (Figs.…”

“…The PHGDH gene encodes phosphoglycerate dehydrogenase, the first enzyme in the serine biosynthesis pathway branching from glycolysis (Fig. 7), and PHGDH is amplified in a subset of human cancers (Locasale et al 2011). PHGDH copy-number gain causes increased PHGDH protein expression and is observed most frequently in melanoma and breast cancer.…”

“…PHGDH copy-number gain causes increased PHGDH protein expression and is observed most frequently in melanoma and breast cancer. Increased PGHDH expression results in increased flux of glucose carbon into serine biosynthesis, and proliferation of cells with PHGDH copy-number gain is blocked by shRNA-mediated knockdown of PHGDH expression (Locasale et al 2011;Possemato et al 2011). Thus, for human cancer cells, at least two different mechanisms exist to increase the flow of glucose carbon into serine biosynthesis: phosphotyrosine growth signal-mediated regulation of PKM2 and PHGDH copy-number gain.…”

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

“…4e). The locus encoding PHGDH is frequently amplified in breast cancer and melanoma 34,35 , and elevated 2HG levels have been detected in primary breast tumors with aggressive features but no IDH mutation 36 . Thus, determining the chirality of 2HG should help elucidate which metabolic pathway contributes to 2HG production in various cancer settings.…”

Glutamine at focus: versatile roles in cancer

“…nucleotides, lipids, proteins, and other cofactors, or using it as an anaplerotic fuel of the TCA cycle and antioxidant defense. These nutrients can be used for the biosysnthesis of proteins, contributing to cancer cell metabolic autonomy [117,119]. In 2013, Maddocks et al showed that p53 is related to serine starvation and oxidative stress, preserving the cellular antioxidant capacity.…”