Differential substrate use in EGF‐ and oncogenic KRAS‐stimulated human mammary epithelial cells. (13th May 2021)

• Record Type: Journal Article
• Authors: 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; Lee, Jennifer; Phanse, Aasavari S.; Kelleher, Joanne K.; Iliopoulos, Othon; Coloff, Jonathan L.; Vander Heiden, Matthew G.; Stephanopoulos, Gregory
• Is Part Of: FEBS journal. Volume 288:Number 19(2021)
• Page Start: 5629
• Page End: 5649
• Publication Date: 2021-05-13
• Subjects: branched‐chain amino acids -- cancer metabolism -- cell growth -- cell proliferation -- KRAS; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.15858
• Languages: English
• ISSNs: 1742-464X

Abstract

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. Abstract : Cancer cells and proliferating nontransformed cells share numerous metabolic phenotypes. Here, we compared the metabolic changes from oncogenic KRAS expression to changes from epidermal growth factor (EGF)‐driven proliferation in human mammary epithelial cells (HMECs). EGF removal dramatically reduced glucose and glutamine consumption alongside growth while maintaining branched‐chain amino acid uptake. However, major metabolic fluxes and sensitivity to metabolic inhibitors were lower in oncogenic KRAS‐driven HMECs versus comparably growing EGF‐driven HMECs.