Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) Is Upregulated in Breast Epithelial–Mesenchymal Transition and Responds to Oxidative Stress

Wang, Qiong; Karvelsson, Sigurður Trausti; Kotronoulas, Aristotelis; Guðjónsson, Þórarinn; Halldórsson, Skarphéðinn; Rolfsson, Óttar

doi:10.1016/j.mcpro.2021.100185

Cited by 17 publications

(16 citation statements)

References 113 publications

(113 reference statements)

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“…Accuracy and validity of the proteomic analysis. The accuracy and validity of the proteomic analysis in this study were confirmed by comparing the current data to our previously generated proteomic data for the D492 EMT model [26]. The correlation between these two datasets was 0.936.…”

Section: Supporting Informationsupporting

confidence: 72%

“…(E) The RNA level of UGDH in all EMT models was consistently higher in the mesenchymal cell lines. (F) The UGDH protein level in the epithelial and mesenchymal cells was confirmed in another data set [ 26 ] and further confirmed in another tumorigenic breast mesenchymal cell line D492HER2. Student's t ‐test, * P < 0.05; ** P < 0.01; *** P < 0.001; n = 3.…”

Section: Resultsmentioning

confidence: 58%

“…3B ). To ensure reproducibility of the proteomic data used in this study (Table S4 ), we compared the current proteomic data set with the previously generated data for the D492 EMT model [ 26 ]. The correlation coefficient of these two data sets was 0.936 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The protocol for SILAC phosphoproteomic analysis was thoroughly described in the other study [ 26 ]. Briefly, protein sample equivalent to 4 mg was dissolved and fractionated, followed by phosphorylated peptide enrichment with MagReSyn‐TiIMAC beads (Resyn Biosciences, Edenvale, Gauteng, South Africa) and Magnetic Rack (DynaMag‐2; Life Technologies, Carlsbad, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…These analyses revealed increased dependency on argininosuccinate lyase (ASL) and enhanced activities of the pentose phosphate pathway, hexosamine biosynthesis and one‐carbon metabolism post‐EMT in the D492 EMT model [23,25]. More recently, we confirmed that metabolic flux through the hexosamine biosynthesis pathway (HBP) increases significantly in mesenchymal cells and that glutamine‐fructose‐6‐phosphate transaminase 2 (GFPT2) in the HBP is associated with breast cancer malignancy [26].…”

Section: Introductionmentioning

confidence: 94%

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UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

et al. 2022

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Metabolic rewiring is one of the indispensable drivers of epithelial–mesenchymal transition (EMT) involved in breast cancer metastasis. In this study, we explored the metabolic changes during spontaneous EMT in three separately established breast EMT cell models using a proteomic approach supported by metabolomic analysis. We identified common proteomic changes, including the expression of CDH1, CDH2, VIM, LGALS1, SERPINE1, PKP3, ATP2A2, JUP, MTCH2, RPL26L1 and PLOD2. Consistently altered metabolic enzymes included the following: FDFT1, SORD, TSTA3 and UDP‐glucose dehydrogenase (UGDH). Of these, UGDH was most prominently altered and has previously been associated with breast cancer patient survival. siRNA‐mediated knock‐down of UGDH resulted in delayed cell proliferation and dampened invasive potential of mesenchymal cells and downregulated expression of the EMT transcription factor SNAI1. Metabolomic analysis revealed that siRNA‐mediated knock‐down of UGDH decreased intracellular glycerophosphocholine (GPC), whereas levels of acetylaspartate (NAA) increased. Finally, our data suggested that platelet‐derived growth factor receptor beta (PDGFRB) signalling was activated in mesenchymal cells. siRNA‐mediated knock‐down of PDGFRB downregulated UGDH expression, potentially via NFkB‐p65. Our results support an unexplored relationship between UGDH and GPC, both of which have previously been independently associated with breast cancer progression.

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Section: Supporting Informationsupporting

confidence: 72%

Section: Resultsmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

et al. 2022

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Cancer‐associated fibroblast expression of glutamine fructose‐6‐phosphate aminotransferase 2 (GFPT2) is a prognostic marker in gastric cancer

Yang

Yin

et al. 2023

The Journal of Pathology CR

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Glutamine fructose‐6‐phosphate aminotransferase 2 (GFPT2) is a rate‐limiting enzyme in hexosamine biosynthesis involved in the occurrence and progress of many cancers. What role it plays in gastric cancer (GC) is still unclear. In this study, transcriptome sequencing data from the Harbin Medical University (HMU)‐GC cohort and The Cancer Genome Atlas (TCGA) dataset were combined with the HMU‐TCGA training cohort to analyze the biological function and clinical significance of GFPT2. The correlation of GFPT2 with immune cells and stromal cells was analyzed in the GC immune microenvironment through transcriptome sequencing data and a public single‐cell sequencing database. In cell lines, GC tissues, and the tissue microarray, GFPT2 protein expression was confirmed by western blotting and immunohistochemistry. The mRNA of GFPT2 was highly expressed in the tumor (p < 0.001), and GC cells and tumors expressed high levels of GFPT2 protein. Compared to low expression, high GFPT2 mRNA expression was associated with higher levels of tumor invasion, higher pathological stages, and poor prognosis (p = 0.02) in GC patients. In a drug susceptibility analysis, GFPT2 mRNA expression was associated with multiple chemotherapeutic drug sensitivity, including docetaxel, paclitaxel, and cisplatin. Gene enrichment analysis found that GFPT2 was mainly primarily involved in the extracellular matrix receptor interaction pathway. The ESTIMATE, CIBERSORT, and ssGSEA algorithms showed that GFPT2 was associated with immune cell infiltration. In addition, GFPT2 was more likely to be expressed within cancer‐associated fibroblasts (CAFs), and high levels of GFPT2 expression were highly correlated with four CAFs scores (all p < 0.05). Finally, a prognostic model to assess the risk of death in GC patients was constructed based on GFPT2 protein expression and lymph node metastasis rate. In conclusion, GFPT2 plays an essential role in the function of CAFs in GC. It can be used as a biomarker to assess GC prognosis and immune infiltration.

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GFPT2 expression is induced by gemcitabine administration and enhances invasion by activating the hexosamine biosynthetic pathway in pancreatic cancer

Miyazaki,

Ariake,

Sato

et al. 2024

Clin Exp Metastasis

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Our previous studies revealed a novel link between gemcitabine (GEM) chemotherapy and elevated glutamine-fructose-6-phosphate transaminase 2 (GFPT2) expression in pancreatic cancer (PaCa) cells. GFPT2 is a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP). HBP can enhance metastatic potential by regulating epithelial-mesenchymal transition (EMT). The aim of this study was to further evaluate the effect of chemotherapy-induced GFPT2 expression on metastatic potential. GFPT2 expression was evaluated in a mouse xenograft model following GEM exposure and in clinical specimens of patients after chemotherapy using immunohistochemical analysis. The roles of GFPT2 in HBP activation, downstream pathways, and cellular functions in PaCa cells with regulated GFPT2 expression were investigated. GEM exposure increased GFPT2 expression in tumors resected from a mouse xenograft model and in patients treated with neoadjuvant chemotherapy (NAC). GFPT2 expression was correlated with post-operative liver metastasis after NAC. Its expression activated the HBP, promoting migration and invasion. Treatment with HBP inhibitors reversed these effects. Additionally, GFPT2 upregulated ZEB1 and vimentin expression and downregulated E-cadherin expression. GEM induction upregulated GFPT2 expression. Elevated GFPT2 levels promoted invasion by activating the HBP, suggesting the potential role of this mechanism in promoting chemotherapy-induced metastasis.

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Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) Is Upregulated in Breast Epithelial–Mesenchymal Transition and Responds to Oxidative Stress

Cited by 17 publications

References 113 publications

UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

UDP‐glucose dehydrogenase expression is upregulated following EMT and differentially affects intracellular glycerophosphocholine and acetylaspartate levels in breast mesenchymal cell lines

Cancer‐associated fibroblast expression of glutamine fructose‐6‐phosphate aminotransferase 2 (GFPT2) is a prognostic marker in gastric cancer

GFPT2 expression is induced by gemcitabine administration and enhances invasion by activating the hexosamine biosynthetic pathway in pancreatic cancer

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