Differential substrate use in EGF- and oncogenic KRAS-stimulated human mammary epithelial cells

被引：3

作者：

Keibler, Mark A. ^{[1
]}

Dong, Wentao ^{[1
]}

Korthauer, Keegan D. ^{[2
,3
,13
,14
]}

Hosios, Aaron M. ^{[4
,5
]}

Moon, Sun Jin ^{[1
]}

Sullivan, Lucas B. ^{[4
,5
]}

Liu, Nian ^{[1
]}

Abbott, Keene L. ^{[4
,5
]}

Arevalo, Orlando D. ^{[1
]}

Ho, Kailing ^{[6
]}

Lee, Jennifer ^{[4
,7
]}

Phanse, Aasavari S. ^{[7
]}

Kelleher, Joanne K. ^{[1
]}

Iliopoulos, Othon ^{[8
,9
]}

Coloff, Jonathan L. ^{[10
,11
]}

Vander Heiden, Matthew G. ^{[4
,5
,12
]}

Stephanopoulos, Gregory ^{[1
]}

机构：

[1] MIT, Dept Chem Engn, Cambridge, MA 02139 USA

[2] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA

[3] Harvard TH Chan Sch Publ Hlth, Boston, MA USA

[4] MIT, Dept Biol, Cambridge, MA USA

[5] MIT, Koch Inst Integrat Canc Res, Cambridge, MA USA

[6] Wellesley Coll, Dept Chem, Wellesley, MA 02181 USA

[7] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA

[8] Massachusetts Gen Hosp, Canc Ctr, Ctr Canc Res, Charlestown, MA USA

[9] Massachusetts Gen Hosp, Div Hematol Oncol, Dept Med, Boston, MA 02114 USA

[10] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA

[11] Univ Illinois, Dept Physiol & Biophys, Canc Ctr, Chicago, IL 60680 USA

[12] Dana Farber Canc Inst, Boston, MA 02115 USA

[13] Univ British Columbia, Dept Stat, Vancouver, BC V6T 1Z4, Canada

[14] British Columbia Childrens Hosp, Res Inst, Vancouver, BC V5Z 4H4, Canada

来源：

FEBS JOURNAL | 2021年 / 288卷 / 19期

关键词：

branched‐ chain amino acids; cancer metabolism; cell growth; cell proliferation; KRAS; CHAIN AMINO-ACIDS; AEROBIC GLYCOLYSIS; GLUTAMINE-METABOLISM; TRANSFORMED-CELLS; GROWTH-FACTORS; CANCER; GLUCOSE; PROTEIN; MASS; REQUIREMENTS;

D O I：

10.1111/febs.15858

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5629 / 5649

页数：21

共 69 条

[1] Parallel labeling experiments with [1,2-13C]glucose and [U-13C]glutamine provide new insights into CHO cell metabolism [J].