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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
Breast cancer
Glutamic acid
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.
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It is part of: Journal of Biological Chemistry, 2016, vol. 291, num. 51, p. 26291-26303
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ISSN: 0021-9258
Appears in Collections:Articles publicats en revistes (Infermeria Fonamental i Medicoquirúrgica)
Articles publicats en revistes (Ciències Fisiològiques)

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