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Transglutaminase 2 reprogramming of glucose metabolism in mammary epithelial cells via activation of inflammatory signaling pathways.
Int J Cancer 2014; 134(12):2798-807IJ

Abstract

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.

Authors+Show Affiliations

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24477458

Citation

Kumar, Santosh, et al. "Transglutaminase 2 Reprogramming of Glucose Metabolism in Mammary Epithelial Cells Via Activation of Inflammatory Signaling Pathways." International Journal of Cancer, vol. 134, no. 12, 2014, pp. 2798-807.
Kumar S, Donti TR, Agnihotri N, et al. Transglutaminase 2 reprogramming of glucose metabolism in mammary epithelial cells via activation of inflammatory signaling pathways. Int J Cancer. 2014;134(12):2798-807.
Kumar, S., Donti, T. R., Agnihotri, N., & Mehta, K. (2014). Transglutaminase 2 reprogramming of glucose metabolism in mammary epithelial cells via activation of inflammatory signaling pathways. International Journal of Cancer, 134(12), pp. 2798-807. doi:10.1002/ijc.28623.
Kumar S, et al. Transglutaminase 2 Reprogramming of Glucose Metabolism in Mammary Epithelial Cells Via Activation of Inflammatory Signaling Pathways. Int J Cancer. 2014 Jun 15;134(12):2798-807. PubMed PMID: 24477458.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transglutaminase 2 reprogramming of glucose metabolism in mammary epithelial cells via activation of inflammatory signaling pathways. AU - Kumar,Santosh, AU - Donti,Taraka R, AU - Agnihotri,Navneet, AU - Mehta,Kapil, Y1 - 2014/01/30/ PY - 2013/07/01/received PY - 2013/10/18/revised PY - 2013/11/04/accepted PY - 2014/1/31/entrez PY - 2014/1/31/pubmed PY - 2014/6/6/medline KW - EMT KW - HIF-1α KW - NF-κB KW - drug resistance KW - metabolism KW - metastasis SP - 2798 EP - 807 JF - International journal of cancer JO - Int. J. Cancer VL - 134 IS - 12 N2 - 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. SN - 1097-0215 UR - https://www.unboundmedicine.com/medline/citation/24477458/Transglutaminase_2_reprogramming_of_glucose_metabolism_in_mammary_epithelial_cells_via_activation_of_inflammatory_signaling_pathways_ L2 - https://doi.org/10.1002/ijc.28623 DB - PRIME DP - Unbound Medicine ER -