TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer.
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.
From the Department of Medical Oncology.
Ying-Hui
YH
Ko
From the Department of Medical Oncology.
Marina
M
Domingo-Vidal
From the Department of Medical Oncology.
Megan
M
Roche
From the Department of Medical Oncology.
Zhao
Z
Lin
From the Department of Medical Oncology.
Diana
D
Whitaker-Menezes
the Department of Pathology, Anatomy, and Cell Biology.
Erin
E
Seifert
the Department of Cancer Biology, and.
Claudia
C
Capparelli
the Department of Pathology, Anatomy, and Cell Biology.
Madalina
M
Tuluc
Department of Pathology, Cooper University Hospital, Camden, New Jersey 08103.
Ruth C
RC
Birbe
the Department of Otolaryngology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Patrick
P
Tassone
the Department of Otolaryngology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Joseph M
JM
Curry
the Department of Physiological Sciences, University of Barcelona, Barcelona 08907, Spain, and.
Àurea
À
Navarro-Sabaté
the Department of Physiological Sciences, University of Barcelona, Barcelona 08907, Spain, and.
Anna
A
Manzano
the Department of Physiological Sciences, University of Barcelona, Barcelona 08907, Spain, and.
Ramon
R
Bartrons
the Department of Medicine, Cardeza Foundation for Hematological Research, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Jaime
J
Caro
From the Department of Medical Oncology, ubaldo.martinez-outschoorn@jefferson.edu.
Ubaldo
U
Martinez-Outschoorn
D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000378:metabolism*; D061986:MCF-7 Cells; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019344:Lactic Acid; D018698:Glutamic Acid; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human
ATP; fructose 2,6-bisphosphate (Fru-2,6-P2); glutamine; glycolysis; hypoxia-inducible factor (HIF); lactic acid; pentose phosphate pathway (PPP); tumor microenvironment