Differential substrate use in EGF‐ and oncogenic KRAS‐stimulated human mammary epithelial cells
Name
10.1111-febs.15858.pdf
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2.38 MB
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Checksum (MD5)
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Author(s)
Keibler, Mark A.
Dong, Wentao
Korthauer, Keegan D.
Hosios, Aaron M.
Moon, Sun Jin
Sullivan, Lucas B.
Liu, Nian
Abbott, Keene L.
Arevalo, Orlando D.
Ho, Kailing
Date Issued
April 3, 2021
Journal
The FEBS Journal
Publisher
Wiley
Citation
Keibler, M.A., Dong, W., Korthauer, K.D., Hosios, A.M., Moon, S.J., Sullivan, L.B., Liu, N., Abbott, K.L., Arevalo, O.D., Ho, K., Lee, J., Phanse, A.S., Kelleher, J.K., Iliopoulos, O., Coloff, J.L., Vander Heiden, M.G. and Stephanopoulos, G. (2021), Differential substrate use in EGF- and oncogenic KRAS-stimulated human mammary epithelial cells. FEBS J, 288: 5629-5649.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
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DOI of Published Version
https://doi.org/10.1111/febs.15858
