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.
Highlights
A subgroup of breast cancers has several metabolic compartments
TP53 inducible glycolysis and apoptosis regulator (TIGAR) upregulates lactate dehydrogenase B (LDH-B), which is the enzyme that converts lactate into pyruvate for mitochondrial metabolism (Fig. 1C) and TIGAR up-regulates glutaminase 1 (GLS1) modestly, which is the rate-limiting enzyme in glutamine catabolism and converts glutamine to glutamate (Fig. 1D)
The current study delineates the role of TIGAR in oxidative phosphorylation (OXPHOS) and glycolytic metabolic reprogramming in breast cancer
Summary
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. 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. TIGAR depletion increases glycolytic flux by increasing the activity of PFK-1 and the glycolytic flux by increasing Fru2,6-P2 levels [7, 14] It is unknown if TIGAR modulates catabolism of other substrates such as lactate and glutamine, which have been shown to be alternate catabolites to glucose for carcinoma cells [1]. We hypothesize that TIGAR expression in carcinoma cells induces aggressive disease with utilization of alternative catabolites to glucose and metabolic compartmentalization
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