Molecule Information

General Information of the Molecule (ID: Mol04072)

• Name: Phosphoglycerate dehydrogenase (PHGDH) ,Homo sapiens
• Synonyms: 2-oxoglutarate reductase; Malate dehydrogenase
• Molecule Type: Protein
• Gene Name: PHGDH
• Gene ID: 26227
• Location: chr1:119648411-119744218[+]
• Sequence:
  MAFANLRKVLISDSLDPCCRKILQDGGLQVVEKQNLSKEELIAELQDCEGLIVRSATKVT
  ADVINAAEKLQVVGRAGTGVDNVDLEAATRKGILVMNTPNGNSLSAAELTCGMIMCLARQ
  IPQATASMKDGKWERKKFMGTELNGKTLGILGLGRIGREVATRMQSFGMKTIGYDPIISP
  EVSASFGVQQLPLEEIWPLCDFITVHTPLLPSTTGLLNDNTFAQCKKGVRVVNCARGGIV
  DEGALLRALQSGQCAGAALDVFTEEPPRDRALVDHENVISCPHLGASTKEAQSRCGEEIA
  VQFVDMVKGKSLTGVVNAQALTSAFSPHTKPWIGLAEALGTLMRAWAGSPKGTIQVITQG
  TSLKNAGNCLSPAVIVGLLKEASKQADVNLVNAKLLVKEAGLNVTTSHSPAAPGEQGFGE
  CLLAVALAGAPYQAVGLVQGTTPVLQGLNGAVFRPEVPLRRDLPLLLFRTQTSDPAMLPT
  MIGLLAEAGVRLLSYQTSLVSDGETWHVMGISSLLPSLEAWKQHVTEAFQFHF
• 3D-structure: PDB ID: 2G76; Classification: Oxidoreductase; Method: X-ray diffraction; Resolution: 1.70 Å
• Function: Catalyzes the reversible oxidation of 3-phospho-D-glycerate to 3-phosphonooxypyruvate, the first step of the phosphorylated L- serine biosynthesis pathway. Also catalyzes the reversible oxidation of 2-hydroxyglutarate to 2-oxoglutarate and the reversible oxidation of (S)-malate to oxaloacetate. .
• Uniprot ID: SERA_HUMAN
• Ensembl ID: ENSG00000092621
• HGNC ID: HGNC:8923

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Bladder cancer [ICD-11: 2C94.0] [1]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Aerobic glycolysis signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: Glycine, serine and threonine metabolism; Activation; hsa00260
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vivo Model: BALB/c female nude mice model; Mus musculus
• Experiment for Molecule Alteration: MS analysis; Western blot assay; Immunohistochemistry
• Experiment for Drug Resistance: IC50 assay; Cell proliferation assay; Migration ability assay; Invasion ability assay; Apoptosis assay
• Mechanism Description: Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1alpha expression. PHGDH downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion.

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Bladder cancer [ICD-11: 2C94.0] [2]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: PHGDH is a key enzyme in serine synthesis and is involved in the synthesis of NADPH and glycine. Activation of serine biosynthesis contributes to cancer cell proliferation, and overexpression of PHGDH has been observed in various cancers [21, 32, 33, 34, 35]. Glycine is necessary for the synthesis of glutathione, which is essential for tumorigenesis [36]. Previous studies have reported that NCT503, a small molecule PHGDH inhibitor, impairs the synthesis of glucose-derived serine and induces apoptosis in BC, thereby suppressing tumor growth [37]. High PHGDH expression is a poor prognostic factor for BC [37]. High PHGDH expression has also been reported as a poor prognostic factor in patients with advanced or recurrent non-small cell lung cancer treated with anti-PD-1/PD-L1 antibodies, which would suggest that PHGDH inhibitors have potential clinical application [39].

Disease Class: Bladder cancer [ICD-11: 2C94.0] [2]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: PHGDH is a key enzyme in serine synthesis and is involved in the synthesis of NADPH and glycine. Activation of serine biosynthesis contributes to cancer cell proliferation, and overexpression of PHGDH has been observed in various cancers [21, 32, 33, 34, 35]. Glycine is necessary for the synthesis of glutathione, which is essential for tumorigenesis [36]. Previous studies have reported that NCT503, a small molecule PHGDH inhibitor, impairs the synthesis of glucose-derived serine and induces apoptosis in BC, thereby suppressing tumor growth [37]. High PHGDH expression is a poor prognostic factor for BC [37]. High PHGDH expression has also been reported as a poor prognostic factor in patients with advanced or recurrent non-small cell lung cancer treated with anti-PD-1/PD-L1 antibodies, which would suggest that PHGDH inhibitors have potential clinical application [40].

Disease Class: Bladder cancer [ICD-11: 2C94.0] [2]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Five-week-old female nude mice (BALB/c nu/nu), with BC cell lines; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor weight assay
• Mechanism Description: PHGDH is a key enzyme in serine synthesis and is involved in the synthesis of NADPH and glycine. Activation of serine biosynthesis contributes to cancer cell proliferation, and overexpression of PHGDH has been observed in various cancers [21, 32, 33, 34, 35]. Glycine is necessary for the synthesis of glutathione, which is essential for tumorigenesis [36]. Previous studies have reported that NCT503, a small molecule PHGDH inhibitor, impairs the synthesis of glucose-derived serine and induces apoptosis in BC, thereby suppressing tumor growth [37]. High PHGDH expression is a poor prognostic factor for BC [37]. High PHGDH expression has also been reported as a poor prognostic factor in patients with advanced or recurrent non-small cell lung cancer treated with anti-PD-1/PD-L1 antibodies, which would suggest that PHGDH inhibitors have potential clinical application [38].

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Bladder cancer [ICD-11: 2C94.0] [1]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Aerobic glycolysis signaling pathway; Regulation; N.A.
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Trypan blue exclusion assay; XTT assay
• Mechanism Description: Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized?HIF1alpha?expression.?PHGDH?downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression.

References

• Ref 1: Targeting metabolic reprogramming to overcome drug resistance in advanced bladder cancer: insights from gemcitabine- and cisplatin-resistant models. Mol Oncol. 2024 Sep;18(9):2196-2211.
• Ref 2: Targeting metabolic reprogramming to overcome drug resistance in advanced bladder cancer: insights from gemcitabine- and cisplatin-resistant models. Mol Oncol. 2024 Sep;18(9):2196-2211.