期刊
INTERNATIONAL JOURNAL OF CANCER
卷 134, 期 12, 页码 2798-2807出版社
WILEY
DOI: 10.1002/ijc.28623
关键词
HIF-1 alpha; drug resistance; NF-kappa B; metastasis; EMT; metabolism
类别
资金
- SK Agarwal Donation Funds [CA016672]
- Indian Council of Medical Research, India
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)-kappa B, which binds to the hypoxia-inducible factor (HIF)-1 alpha promoter and induces its expression even under normoxic conditions. TG2/NF-kappa B-induced increase in HIF-1 alpha expression was associated with increased glucose uptake, increased lactate production and decreased oxygen consumption by mitochondria. Experimental suppression of TG2 attenuated HIF-1 alpha expression and reversed downstream events in mammary epithelial cells. Moreover, downregulation of p65/RelA or HIF-1 alpha 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据