PMID- 31532771
OWN - NLM
STAT- MEDLINE
DCOM- 20200309
LR  - 20200309
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 14
IP  - 9
DP  - 2019
TI  - EGF receptor stimulation shifts breast cancer cell glucose metabolism toward 
      glycolytic flux through PI3 kinase signaling.
PG  - e0221294
LID - 10.1371/journal.pone.0221294 [doi]
LID - e0221294
AB  - 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.
FAU - Jung, Kyung-Ho
AU  - Jung KH
AD  - Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University 
      School of Medicine, Seoul, Korea.
AD  - Department of Health Science and Technology, SAIHST, Sungkyunkwan University, 
      Seoul, Korea.
FAU - Lee, Eun Jeong
AU  - Lee EJ
AD  - Department of Nuclear Medicine, Seoul Medical Center, Seoul, Korea.
FAU - Park, Jin Won
AU  - Park JW
AD  - Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University 
      School of Medicine, Seoul, Korea.
AD  - Department of Health Science and Technology, SAIHST, Sungkyunkwan University, 
      Seoul, Korea.
FAU - Lee, Jin Hee
AU  - Lee JH
AD  - Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University 
      School of Medicine, Seoul, Korea.
AD  - Department of Health Science and Technology, SAIHST, Sungkyunkwan University, 
      Seoul, Korea.
FAU - Moon, Seung Hwan
AU  - Moon SH
AD  - Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University 
      School of Medicine, Seoul, Korea.
FAU - Cho, Young Seok
AU  - Cho YS
AD  - Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University 
      School of Medicine, Seoul, Korea.
FAU - Lee, Kyung-Han
AU  - Lee KH
AUID- ORCID: 0000-0003-3565-5536
AD  - Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University 
      School of Medicine, Seoul, Korea.
AD  - Department of Health Science and Technology, SAIHST, Sungkyunkwan University, 
      Seoul, Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190918
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0Z5B2CJX4D (Fluorodeoxyglucose F18)
RN  - 33X04XA5AT (Lactic Acid)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Breast Neoplasms/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - ErbB Receptors/metabolism
MH  - Female
MH  - Fluorodeoxyglucose F18/metabolism
MH  - Glucose/*metabolism
MH  - *Glycolysis
MH  - Humans
MH  - Lactic Acid/metabolism
MH  - MCF-7 Cells
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation
MH  - Signal Transduction
PMC - PMC6750601
COIS- The authors have declared that no competing interests exist.
EDAT- 2019/09/19 06:00
MHDA- 2020/03/10 06:00
PMCR- 2019/09/18
CRDT- 2019/09/19 06:00
PHST- 2019/03/25 00:00 [received]
PHST- 2019/08/03 00:00 [accepted]
PHST- 2019/09/19 06:00 [entrez]
PHST- 2019/09/19 06:00 [pubmed]
PHST- 2020/03/10 06:00 [medline]
PHST- 2019/09/18 00:00 [pmc-release]
AID - PONE-D-19-08574 [pii]
AID - 10.1371/journal.pone.0221294 [doi]
PST - epublish
SO  - PLoS One. 2019 Sep 18;14(9):e0221294. doi: 10.1371/journal.pone.0221294. 
      eCollection 2019.