EGF receptor stimulation shifts breast cancer cell glucose metabolism toward glycolytic flux through PI3 kinase signaling
Autoři:
Kyung-Ho Jung aff001; Eun Jeong Lee aff003; Jin Won Park aff001; Jin Hee Lee aff001; Seung Hwan Moon aff001; Young Seok Cho aff001; Kyung-Han Lee aff001
Působiště autorů:
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
aff001; Department of Health Science and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea
aff002; Department of Nuclear Medicine, Seoul Medical Center, Seoul, Korea
aff003
Vyšlo v časopise:
PLoS ONE 14(9)
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pone.0221294
Souhrn
Breast cancers that express epidermal growth factor (EGF) receptors (EGFRs) are associated with poor prognosis. Our group recently showed in breast cancer patients that EGFR expression is strongly correlated with high tumor uptake of the glucose analogue, 18F-fluorodeoxyglucose (FDG). Here, we explored the cellular mechanism and signaling pathways that can explain the relation between EGFR and breast cancer cell glucose metabolism. FDG uptake, lactate production and hexokinase (HK) activity were measured, and proliferation assays and western blots were performed. EGF stimulated an increase of FDG uptake in EGFR-positive T47D and MDA-MB-468 cells, but not in MCF-7 cells. In T47D cells, the effect was dose-dependent and was accompanied by increased lactate production, indicating a shift toward glycolytic flux. This metabolic response occurred through enhanced HK activity and upregulated glucose transporter 1 (GLUT1) expression. EGFR stimulation also increased T47D cell proliferation. Blocking EGFR activation with BIBX1382 or gefitinib completely abolished both FDG uptake and proliferation effects. EGFR stimulation induced MAP kinase (MAPK) and PI3 kinase (PI3K) activation. Increased cell proliferation by EGFR stimulation was completely abolished by MAPK inhibition with PD98059 or by PI3K inhibition with LY294002. Increased FDG uptake was also completely abrogated by PI3K inhibition but was uninfluenced by MAPK inhibition. These findings suggest that the association between breast tumor EGFR expression and high FDG uptake might be contributed by stimulation of the PI3K pathway downstream of EGFR activation. This was in contrast to EGFR-mediated cell proliferation that required MAPK as well as PI3K signaling.
Klíčová slova:
Biology and life sciences – Cell biology – Biochemistry – Physical sciences – Chemistry – Enzymology – Enzymes – Proteins – Cell processes – Medicine and health sciences – Chemical compounds – Cellular structures and organelles – Organic compounds – Carbohydrates – Monosaccharides – Organic chemistry – Metabolism – Carbohydrate metabolism – Glucose metabolism – Oncology – Cancers and neoplasms – Cell membranes – Membrane proteins – Signal transduction – Glucose – Cell signaling – Signaling cascades – Cell proliferation – Breast tumors – Breast cancer – Hexokinases – MAPK signaling cascades – EGFR signaling
Zdroje
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