Serine and glycine metabolism in cancer

Amelio, Ivano; Cutruzzolà, Francesca; Антонов, А.; Agostini, Massimiliano; Melino, Gerry

doi:10.1016/j.tibs.2014.02.004

Cited by 845 publications

(759 citation statements)

References 58 publications

(48 reference statements)

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“…Furthermore, downregulation of cMyc by shRNAs attenuated nutrient deprivation-induced high expression of SSP enzymes in Hep3B cells ( Figure 2E), suggesting that cMyc is critical for nutrient starvation-induced SSP activation. Finally, NMR analysis using 13 C-labeled glucose demonstrated that 13 C incorporation into both glycine and GSH was significantly increased in cMyc-overexpressing Hep3B cells ( Figure 2F), further demonstrating that cMyc promotes SSP activation, driving metabolic flux to glycine and GSH. Our data also showed that cMyc regulates glutaminolysis and glycolysis enzymes both at mRNA and protein levels in Hep3B cells (Supplementary information, Figure S1D-S1F).…”

Section: The Pathways Leading To Serine Biosynthesis Are Activated Unmentioning

confidence: 83%

“…As shown in Figure 3L, 13 C incorporation into both AMP and UMP was significantly increased in cMycor PSPH-overexpressing cells, and knocking down cMyc or PSPH markedly reduced 13 C incorporation into both AMP and UMP, suggesting that both cMyc and PSPH facilitate nucleotide synthesis, which could possibly account for the decreased S phase populations in PSPH-deficient cells ( Figure 3J). Importantly, knockdown of PSPH markedly inhibited cell proliferation in Hep3B and SK-hep-1 cells ( Figure 3M and Supplementary information, Figure S2E).…”

Section: Cmyc-mediated Psph Expression and Ssp Activation Are Criticamentioning

confidence: 86%

“…Interestingly, it has been reported recently that these two amino acids play important roles in cancer progression [13][14][15][16]. Glycolytic metabolism of glucose provides metabolite of 3-PG which can be catalyzed by 3-phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1) and phosphoserine phosphatase (PSPH) into serine, during which glycine is produced through the inter-conversion between serine and glycine by serine hydroxymethyltransferase (SHMT1/2) [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

et al. 2015

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Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed conditions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramatically activated serine biosynthesis pathway (SSP) that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMyc led to elevated glutathione (GSH) production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially under nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase (PSPH), the final rate-limiting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and importantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma (HCC) patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activation, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions.

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Section: The Pathways Leading To Serine Biosynthesis Are Activated Unmentioning

confidence: 83%

Section: Cmyc-mediated Psph Expression and Ssp Activation Are Criticamentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

et al. 2015

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“…The GSH-dependent antioxidant response of cancer cells may benefit depending on the availability of serine, which can be transformed into glycine through the serine hydroxymethyltransferase (SHMT). [104][105][106] Interestingly, it has been demonstrated that cancer cells lacking p53 are protected from oxidative stress-induced by serine depletion in the presence of p73, a p53 family member that has the ability to drive serine biosynthesis de novo 107,108 and to increase the pentose phosphate shunt and nucleotide biosynthesis via G6PD. 109,110 Thus, the p73 overexpression detected in various primary RMS samples 111 may have an important role for oxidative stress resistance.…”

Section: Oxidative Stress Pathwaysmentioning

confidence: 99%

Uncovering metabolism in rhabdomyosarcoma

Monti

Fanzani

2016

Cell Cycle

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Rhabdomyosarcoma (RMS) is a myogenic tumor classified as the most frequent soft tissue sarcoma affecting children and adolescents. The histopathological classification includes five different histotypes, with two most predominant referred as to embryonal and alveolar, the latter being characterized by adverse outcome. The current molecular classification identifies two major subsets, those harboring the fused Pax3-Foxo1 transcription factor generating from a recurrent specific translocation (fusion-positive RMS), and those lacking this signature but harboring mutations in the RAS/PI3K/AKT signalling axis (fusion-negative RMS). Since little attention has been devoted to RMS metabolism until now, in this review we summarize the “state of art” of metabolism and discuss how some of the molecular signatures found in this cancer, as observed in other more common tumors, can predict important metabolic challenges underlying continuous cell growth, oxidative stress resistance and metastasis, which could be the subject of future targeted therapies

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“…As such, PEPCK's role can be exploited for cancer therapy. Most recently, the role of serine and glycine has been appreciated in cancer [116]. Cancer cells uptake glucose and glutamine to produce serine and glycine, using intermediate metabolites of glycolysis and glutaminolysis.…”

Section: Oncometabolites For Synthesis Of Biomass and Malignancymentioning

confidence: 99%

Glutamine at focus: versatile roles in cancer

2015

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Your article is protected by copyright and all rights are held exclusively by International Society of Oncology and BioMarkers (ISOBM).Abstract During the past decade, a heightened understanding of metabolic pathways in cancer has significantly increased. It is recognized that many tumor cells are genetically programmed and have involved an abnormal metabolic state. Interestingly, this increased metabolic autonomy generates dependence on various nutrients such as glucose and glutamine. Both of these components participate in various facets of metabolic activity that allow for energy production, synthesis of biomass, antioxidant defense, and the regulation of cell signaling. Here, we outline the emerging data on glutamine metabolism and address the molecular mechanisms underlying glutamine-induced cell survival. We also discuss novel therapeutic strategies to exploit glutamine addiction of certain cancer cell lines.

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Serine and glycine metabolism in cancer

Cited by 845 publications

References 58 publications

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

Uncovering metabolism in rhabdomyosarcoma

Glutamine at focus: versatile roles in cancer

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