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http://hdl.handle.net/2445/177308
Title: | TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer |
Author: | Ko, Ying-Hui Domingo-Vidal, Marina Roche, Megan Lin, Zhao Whitaker-Menezes, Diana Seifert, Erin Capparelli, Claudia Tuluc, Madalina Birbe, Ruth C. Tassone, Patrick Curry, Joseph M. Navarro i Sabaté, Àurea Manzano Cuesta, Anna Bartrons Bach, Ramon Caro, Jaime Martinez-Outschoorn, Ubaldo E. |
Keywords: | Càncer de mama Àcid glutàmic Metabolisme Breast cancer Glutamic acid Metabolism |
Issue Date: | 16-Dec-2016 |
Publisher: | American Society for Biochemistry and Molecular Biology |
Abstract: | A subgroup of breast cancers has several metabolic compartments. The mechanisms by which metabolic compartmentalization develop in tumors are poorly characterized. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. Hence we set out to determine the effects of TIGAR expression on breast carcinoma and fibroblast glycolytic phenotype and tumor growth. The overexpression of this bisphosphatase in carcinoma cells induces expression of enzymes and transporters involved in the catabolism of lactate and glutamine. Carcinoma cells overexpressing TIGAR have higher oxygen consumption rates and ATP levels when exposed to glutamine, lactate, or the combination of glutamine and lactate. Coculture of TIGAR overexpressing carcinoma cells and fibroblasts compared with control cocultures induce more pronounced glycolytic differences between carcinoma and fibroblast cells. Carcinoma cells overexpressing TIGAR have reduced glucose uptake and lactate production. Conversely, fibroblasts in coculture with TIGAR overexpressing carcinoma cells induce HIF (hypoxia-inducible factor) activation with increased glucose uptake, increased 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), and lactate dehydrogenase-A expression. We also studied the effect of this enzyme on tumor growth. TIGAR overexpression in carcinoma cells increases tumor growth in vivo with increased proliferation rates. However, a catalytically inactive variant of TIGAR did not induce tumor growth. Therefore, TIGAR expression in breast carcinoma cells promotes metabolic compartmentalization and tumor growth with a mitochondrial metabolic phenotype with lactate and glutamine catabolism. Targeting TIGAR warrants consideration as a potential therapy for breast cancer. |
Note: | Reproducció del document publicat a: https://doi.org/10.1074/jbc.M116.740209 |
It is part of: | Journal of Biological Chemistry, 2016, vol. 291, num. 51, p. 26291-26303 |
URI: | http://hdl.handle.net/2445/177308 |
Related resource: | https://doi.org/10.1074/jbc.M116.740209 |
ISSN: | 0021-9258 |
Appears in Collections: | Articles publicats en revistes (Infermeria Fonamental i Clínica) Articles publicats en revistes (Ciències Fisiològiques) |
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694270.pdf | 3.41 MB | Adobe PDF | View/Open |
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