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1,25‐dihydroxyvitamin D regulation of pyruvate carboxylase and glucose addiction in MCF10A‐ ras human breast epithelial cells
Author(s) -
Zheng Wei,
Teegarden Dorothy
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.639.19
Subject(s) - glycolysis , carbohydrate metabolism , cell cycle , endocrinology , medicine , cell growth , warburg effect , glucose uptake , pyruvate carboxylase , metabolism , oncogene , citric acid cycle , cell , chemistry , biology , biochemistry , enzyme , insulin
The mechanism and biological consequence of 1,25‐dihydroxyvitamin D (1,25D) regulation of glucose metabolism in progression to cancer (Warburg effect) was investigated. Our previous studies show that 1,25D shifts glucose metabolism towards reduced glycolysis and lactate production and reduced flux through the TCA cycle in ras ‐oncogene transfected MCF10A ( ras ) cells, a model of early breast cancer progression. In the current studies, 1,25D reduced the mRNA (by 55%) and protein (by 35%) expression of pyruvate carboxylase (PC), a key enzyme for the anaplerosis of the TCA cycle, suggesting 1,25D may regulate glucose metabolism via PC. 1,25D inhibited growth, reducing ras cell number by 44% in media containing 5 mM glucose. Glucose restriction to 1 mM further reduced ras cell number by 39% compared to 5 mM glucose, indicating the ras cell dependence on glucose (addiction). However, 1,25D prevented the reduction in cell number at 1 mM glucose, suggesting 1,25D may reduce ras cell glucose addiction. Consistent with these results, flow cytometry analysis showed 1,25D treatment prevented the increase in G1 cell cycle arrest at 1 mM glucose noted in ras cells, further supporting that 1,25D reduces glucose addiction. These results suggest 1,25D regulation of glucose metabolism during early cancer progression has important biological consequences which may be mediated via PC. Grant Funding Source : NIH R25CA128770