Phosphoglycerate dehydrogenase is a novel predictor for poor prognosis in gastric cancer

Xian, Yun; Zhang, Shu; Wang, Xudong; Jin, Qin; Wang, Wei; Wu, Hanjiang

doi:10.2147/ott.s105787

Cited by 26 publications

(8 citation statements)

References 35 publications

(48 reference statements)

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“…The lack of serine in the TME caused by the upregulation of PHGDH can impair the function of immune T cells. The expression of PHGDH was negatively correlated with the 5-year survival rate of GC patients, and multivariate analysis shows that it was an independent prognostic factor for the prognosis of GC ( Xian et al, 2016 ). However, the effect of high expression of PHGDH on the GC TME and immune cells has not yet been studied.…”

Section: Discussionmentioning

confidence: 97%

Identification of 14 Differentially-Expressed Metabolism-Related Genes as Potential Targets of Gastric Cancer by Integrated Proteomics and Transcriptomics

Zhang

Liu²,

Wei³

et al. 2022

Front. Cell Dev. Biol.

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Although research on the metabolism related to gastric cancer (GC) is gradually gaining increasing interest, there are few studies regarding metabolism-related genes in GC. Understanding the characteristic changes of metabolism-related genes at the transcriptional and protein levels in GC will help us to identify new biomarkers and novel therapeutic targets. We harvested six pairs of samples from GC patients and evaluated the differentially expressed proteins using mass spectrometry-based proteomics. RNA sequencing was conducted simultaneously to detect the corresponding expression of mRNAs, and bioinformatics analysis was used to reveal the correlation of significant differentially expressed genes. A total of 57 genes were observed to be dysregulated both in proteomics and transcriptomics. Bioinformatics analysis showed that these differentially expressed genes were significantly associated with regulating metabolic activity. Further, 14 metabolic genes were identified as potential targets for GC patients and were related to immune cell infiltration. Moreover, we found that dysregulation of branched-chain amino acid transaminase 2 (BCAT2), one of the 14 differentially expressed metabolism-related genes, was associated with the overall survival time in GC patients. We believe that this study provides comprehensive information to better understand the mechanism underlying the progression of GC metastasis and explores the potential therapeutic and prognostic metabolism-related targets for GC.

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Section: Discussionmentioning

confidence: 97%

Identification of 14 Differentially-Expressed Metabolism-Related Genes as Potential Targets of Gastric Cancer by Integrated Proteomics and Transcriptomics

Zhang

Liu²,

Wei³

et al. 2022

Front. Cell Dev. Biol.

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“…various types of cancer (eg, breast, 29 bladder, 30 glioma, 31 cervical, 32 melanoma, 33 non-small-cell lung, 34 colorectal 11 and gastric 35 ), dysregulating serine metabolism and contributing to tumor progression. Inhibition of PHGDH activity by si-RNA or inhibitors can disrupt the serine synthesis pathway and restrain the growth and proliferation of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

<p>Inhibition of Serine Metabolism Promotes Resistance to Cisplatin in Gastric Cancer</p>

Zhao

Tang

et al. 2020

OTT

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Background: Serine provides important precursors of protein, lipid, and nucleotide synthesis needed for tumor cell growth. Phosphoglycerate dehydrogenase (PHGDH), a key ratelimiting enzyme in the serine de novo synthesis pathway, is highly expressed in many tumor types (including gastric cancer) and negatively correlated with overall survival. Cisplatin is a chemotherapeutic drug commonly used in the treatment of gastric cancer. In this study, we mainly investigated the relationship between serine metabolism and resistance to cisplatin in gastric cancer cells, as well as the regulatory mechanism involved in this process. Materials and Methods: We determined the effect of different concentrations of serine or a PHGDH inhibitor combined with cisplatin or oxaliplatin on the viability and apoptosis of SGC7901, BGC823, and MGC803 cells via the Cell Counting Kit-8 and Hoechst 33258 staining, respectively. Western blotting was utilized to detect the relative protein expression. Furthermore, we investigated DNA damage through the micrococcal nuclease sensitivity assay detected using agarose gels. Results: We found that reduced concentrations of serine or inhibition of PHGDH hindered the toxicity and pro-apoptotic effects of cisplatin on gastric cancer cells. Moreover, the addition of serine could reverse the sensitivity of gastric cancer cells to cisplatin. Moreover, we found that DNA damage was reduced by treatment with PHGDH inhibitor NCT-503 or CBR-5884. Inhibition of serine metabolism induced a decrease in H3K4 tri-methylation, which was reversed by JIB-04 (inhibitor of H3K4 demethylase). The tolerance of gastric cancer cells to cisplatin was relieved by JIB-04. Through micrococcal nuclease experiments, we further found that inhibiting the activity of PHGDH strengthened chromatin tightness. Conclusion: Inhibition of serine metabolism reduced H3K4 tri-methylation and increased the density of chromatin, which leads to decreased toxicity and pro-apoptotic effect of platinum chemotherapeutic drugs on gastric cancer cells.

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“…The product is then subsequently converted into phosphoserine via transamination by phosphoserine aminotransferase (PSAT1) and, ultimately, to serine via phosphate ester hydrolysis and the enzyme PSPH, serine is also an activator of PKM2 in the glycolysis. Over recent years, an increasing number of studies have focused upon PHGDH in cancer research, which is found to exhibit elevation and controlled flux throughout the serine biosynthetic pathway in cancer cells [ 21 ]. Interestingly, The overexpression of PHGDH is often associated with progression of cancers, and the inhibitors of PHGDH reduce the glycolysis and suppress the growth of cancers [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Down regulating PHGDH affects the lactate production of sertoli cells in varicocele

Guo

Huang

Yang

et al. 2020

Reprod Biol Endocrinol

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Background: Although varicocele is considered to be one of the leading causes of male infertility, the precise mechanism underlying how varicocele leads to male infertility is not completely understood. We found the lactate concentration on the varicocele side of the patients was decreased compare with peripheral venous blood. In the testicles, the lactate produced by the sertoli cells through the glycolysis pathway provides most of the energy needed for spermatogenesis, the reduction of lactate will affect spermatogenesis. The objective of this study was to investigate the mechanism of this abnormal energy metabolism phenomenon in varicocele. Methods: In this study, we collected the testicular tissue from patients with varicocele, the glycolysis related proteins PHGDH was identified by iTRAQ proteomics technology. Experimental rat varicocele model was constructed according to our new clip technique, the mRNA and protein expression levels of PHGDH were examined with qRT-PCR and Western blotting. We constructed a sertoli cell of PHGDH down-regulation model, and then detected the glucose consumption, LDH activities and lactate production in the sertoli cells. Western blot was conducted to investigate the effects of PHGDH on the expression of phosphoserine phosphatase (PSPH) and Pyruvate kinase M2 (PKM2). Flow cytometry was used to detect the cell apoptosis and cell cycle in sertoli cells. Results: The results showed that testicular protein PHGDH was down-regulated in patients with varicocele and in experimental rat varicocele model. Down-regulation of PHGDH in sertoli cells significantly decreased the glucose consumption, LDH activities and lactate production in the sertoli cells, indicating that the low expression of PHGDH ultimately led to a decrease in lactate production by affecting the glycolysis. The Western blot results showed that the down-regulation of PHGDH significantly reduced the expression of pathway protein PSPH and PKM2, leading to the reduction of lactate production. Moreover, PHGDH knockdown can promote apoptosis and inhibit cell cycle to affect cell growth. Conclusions: Overall, we conformed that varicocele lead to the decreasing of testis lactate production. Downregulation of PHGDH in sertoli cells may mediate the process of abnormal glucose metabolism. Our study provide new insight into the mechanisms underlying metabolism-associated male infertility and suggests a novel therapeutic target for male infertility.

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Phosphoglycerate dehydrogenase is a novel predictor for poor prognosis in gastric cancer

Cited by 26 publications

References 35 publications

Identification of 14 Differentially-Expressed Metabolism-Related Genes as Potential Targets of Gastric Cancer by Integrated Proteomics and Transcriptomics

Identification of 14 Differentially-Expressed Metabolism-Related Genes as Potential Targets of Gastric Cancer by Integrated Proteomics and Transcriptomics

<p>Inhibition of Serine Metabolism Promotes Resistance to Cisplatin in Gastric Cancer</p>

Down regulating PHGDH affects the lactate production of sertoli cells in varicocele

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