1. Differential substrate use in EGF- and oncogenic KRAS-stimulated human mammary epithelial cells.
- Author
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Keibler MA, Dong W, Korthauer KD, Hosios AM, Moon SJ, Sullivan LB, Liu N, Abbott KL, Arevalo OD, Ho K, Lee J, Phanse AS, Kelleher JK, Iliopoulos O, Coloff JL, Vander Heiden MG, and Stephanopoulos G
- Subjects
- Animals, Breast growth & development, Breast pathology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Proliferation genetics, Epithelial Cells metabolism, Epithelial Cells pathology, Female, Gene Expression Regulation, Neoplastic genetics, Glucose metabolism, Glucose Transporter Type 1 antagonists & inhibitors, Glutamic Acid metabolism, Glutamine metabolism, Humans, Lactic Acid metabolism, Mammary Glands, Human growth & development, Mammary Glands, Human pathology, Tumor Cells, Cultured, Breast Neoplasms genetics, Carcinogenesis genetics, Epidermal Growth Factor genetics, Glucose Transporter Type 1 genetics, Proto-Oncogene Proteins p21(ras) genetics
- Abstract
Many metabolic phenotypes in cancer cells are also characteristic of proliferating nontransformed mammalian cells, and attempts to distinguish between phenotypes resulting from oncogenic perturbation from those associated with increased proliferation are limited. Here, we examined the extent to which metabolic changes corresponding to oncogenic KRAS expression differed from those corresponding to epidermal growth factor (EGF)-driven proliferation in human mammary epithelial cells (HMECs). Removal of EGF from culture medium reduced growth rates and glucose/glutamine consumption in control HMECs despite limited changes in respiration and fatty acid synthesis, while the relative contribution of branched-chain amino acids to the TCA cycle and lipogenesis increased in the near-quiescent conditions. Most metabolic phenotypes measured in HMECs expressing mutant KRAS were similar to those observed in EGF-stimulated control HMECs that were growing at comparable rates. However, glucose and glutamine consumption as well as lactate and glutamate production were lower in KRAS-expressing cells cultured in media without added EGF, and these changes correlated with reduced sensitivity to GLUT1 inhibitor and phenformin treatment. Our results demonstrate the strong dependence of metabolic behavior on growth rate and provide a model to distinguish the metabolic influences of oncogenic mutations and nononcogenic growth., (© 2021 Federation of European Biochemical Societies.)
- Published
- 2021
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