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

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


Title: Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) Is Upregulated in Breast Epithelial-Mesenchymal Transition and Responds to Oxidative Stress
Author: Wang, Qiong
Karvelsson, Sigurdur Trausti
Kotronoulas, Aristotelis
Gudjonsson, Thorarinn   orcid.org/0000-0001-9645-9665
Halldorsson, Skarphedinn   orcid.org/0000-0003-4337-9252
Rolfsson, Ottar
Date: 2022-02-01
Language: English
Scope: 100185
University/Institute: University of Iceland
Department: Faculty of Medicine
Clinical Laboratory Services, Diagnostics and Blood Bank
Series: Molecular and Cellular Proteomics; 21(2)
ISSN: 1535-9476
DOI: https://doi.org/10.1016/j.mcpro.2021.100185
Subject: Breast Neoplasms; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition/physiology; Female; Fructosephosphates; Glutamine/metabolism; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/metabolism; Glycogen Synthase Kinase 3/metabolism; Humans; Oxidative Stress; Transaminases/metabolism; Analytical Chemistry; Molecular Biology; Biochemistry
URI: https://hdl.handle.net/20.500.11815/3757

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Citation:

Wang , Q , Karvelsson , S T , Kotronoulas , A , Gudjonsson , T , Halldorsson , S & Rolfsson , O 2022 , ' Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) Is Upregulated in Breast Epithelial-Mesenchymal Transition and Responds to Oxidative Stress ' , Molecular and Cellular Proteomics , vol. 21 , no. 2 , 100185 , pp. 100185 . https://doi.org/10.1016/j.mcpro.2021.100185

Abstract:

Breast cancer cells that have undergone partial epithelial- mesenchymal transition (EMT) are believed to be more invasive than cells that have completed EMT. To study metabolic reprogramming in different mesenchymal states, we analyzed protein expression following EMT in the breast epithelial cell model D492 with single-shot LFQ supported by a SILAC proteomics approach. The D492 EMT cell model contains three cell lines: the epithelial D492 cells, the mesenchymal D492M cells, and a partial mesenchymal, tumorigenic variant of D492 that overexpresses the oncogene HER2. The analysis classified the D492 and D492M cells as basal-like and D492HER2 as claudin-low. Comparative analysis of D492 and D492M to tumorigenic D492HER2 differentiated metabolic markers of migration from those of invasion. Glutamine-fructose-6- phosphate transaminase 2 (GFPT2) was one of the top dysregulated enzymes in D492HER2. Gene expression analysis of the cancer genome atlas showed that GFPT2 expression was a characteristic of claudin-low breast cancer. siRNA-mediated knockdown of GFPT2 influenced the EMT marker vimentin and both cell growth and invasion in vitro and was accompanied by lowered metabolic flux through the hexosamine biosynthesis pathway (HBP). Knockdown of GFPT2 decreased cystathionine and sulfide: quinone oxidoreductase (SQOR) in the transsulfuration pathway that regulates H2S production and mitochondrial homeostasis. Moreover, GFPT2 was within the regulation network of insulin and EGF, and its expression was regulated by reduced glutathione (GSH) and suppressed by the oxidative stress regulator GSK3-β. Our results demonstrate that GFPT2 controls growth and invasion in the D492 EMT model, is a marker for oxidative stress, and associated with poor prognosis in claudin-low breast cancer.

Description:

Funding Information: com. This work was funded by Icelandic Center for Research (RANNÍS, 163254-052) and Göngum Saman 2018. Funding Information: We are grateful for the contributions from Douglas Lamont and Amy Tavendale at the "Finger- Prints" Proteomics Facility, College of Life Sciences, MSI/ WTB/JBC Complex, University of Dundee, for their help with the proteomic and phosphoproteomic data collection and analysis. The graphical abstract was created with BioRender.com. This work was funded by Icelandic Center for Research (RANNIS, 163254-052) and Göngum Saman 2018. Publisher Copyright: © 2021 THE AUTHORS.

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