TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer
TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer
复制标题
DOI：
10.1074/jbc.m116.740209
复制
发表时间：
2016-12-16
影响因子：
4.8
通讯作者：
Martinez-Outschoorn, Ubaldo
中科院分区：
文献类型：
--
作者：
Ko, Ying-Hui;Domingo-Vidal, Marina;Martinez-Outschoorn, Ubaldo
乳腺癌的一个亚组有几个代谢区室。肿瘤中代谢区室化发展的机制尚不清楚。TP 53诱导型糖酵解和凋亡调节因子（TIGAR）是一种减少糖酵解的双磷酸酶，并且在大多数人乳腺癌的癌细胞中高度表达。因此，我们着手确定TIGAR表达对乳腺癌和成纤维细胞糖酵解表型和肿瘤生长的影响。这种双磷酸酶在癌细胞中的过表达诱导参与乳酸和谷氨酰胺的催化的酶和转运蛋白的表达。当暴露于谷氨酰胺、乳酸盐或谷氨酰胺和乳酸盐的组合时，过表达TIGAR的癌细胞具有较高的耗氧速率和ATP水平。与对照共培养物相比，过表达TIGAR的癌细胞和成纤维细胞的共培养物诱导癌细胞和成纤维细胞之间更显著的糖酵解差异。过表达TIGAR的癌细胞具有减少的葡萄糖摄取和乳酸产生。相反，与TIGAR过表达癌细胞共培养的成纤维细胞诱导HIF（缺氧诱导因子）活化，葡萄糖摄取增加，6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶-3（PFKFB 3）和乳酸脱氢酶-A表达增加。我们还研究了这种酶对肿瘤生长的影响。癌细胞中的TIGAR过表达增加体内肿瘤生长，增殖速率增加。然而，TIGAR的无催化活性变体不诱导肿瘤生长。因此，乳腺癌细胞中的TIGAR表达促进代谢区室化和肿瘤生长，具有乳酸盐和谷氨酰胺催化剂的线粒体代谢表型。靶向TIGAR值得考虑作为乳腺癌的潜在疗法。
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.