Transglutaminase 2 reprogramming of glucose metabolism in mammary epithelial cells via activation of inflammatory signaling pathways.
Aberrant glucose metabolism characterized by high levels of glycolysis, even in the presence of oxygen, is an important hallmark of cancer. This metabolic reprogramming referred to as the Warburg effect is essential to the survival of tumor cells and provides them with substrates required for biomass generation. Molecular mechanisms responsible for this shift in glucose metabolism remain elusive. As described herein, we found that aberrant expression of the proinflammatory protein transglutaminase 2 (TG2) is an important regulator of the Warburg effect in mammary epithelial cells. Mechanistically, TG2 regulated metabolic reprogramming by constitutively activating nuclear factor (NF)-κB, which binds to the hypoxia-inducible factor (HIF)-1α promoter and induces its expression even under normoxic conditions. TG2/NF-κB-induced increase in HIF-1α expression was associated with increased glucose uptake, increased lactate production and decreased oxygen consumption by mitochondria. Experimental suppression of TG2 attenuated HIF-1α expression and reversed downstream events in mammary epithelial cells. Moreover, downregulation of p65/RelA or HIF-1α expression in these cells restored normal glucose uptake, lactate production, mitochondrial respiration and glycolytic protein expression. Our results suggest that aberrant expression of TG2 is a master regulator of metabolic reprogramming and facilitates metabolic alterations in epithelial cells even under normoxic conditions. A TG2-induced shift in glucose metabolism helps breast cancer cells to survive under stressful conditions and promotes their metastatic competence.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Santosh
S
Kumar
Taraka R
TR
Donti
Navneet
N
Agnihotri
Kapil
K
Mehta
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000235:genetics; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology; D019344:Lactic Acid / Q000096:biosynthesis; D061986:MCF-7 Cells; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000378:metabolism*; D011503:Transglutaminases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D019344:Lactic Acid; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D005947:Glucose; D010100:Oxygen
EMT; HIF-1α; NF-κB; drug resistance; metabolism; metastasis