PMID- 27285995
OWN - NLM
STAT- MEDLINE
DCOM- 20170718
LR  - 20220317
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 6
DP  - 2016
TI  - Anti-Breast Cancer Potential of Quercetin via the Akt/AMPK/Mammalian Target of 
      Rapamycin (mTOR) Signaling Cascade.
PG  - e0157251
LID - 10.1371/journal.pone.0157251 [doi]
LID - e0157251
AB  - The Akt/adenosine monophosphate protein kinase (AMPK)/mammalian target of 
      rapamycin (mTOR) pathway has emerged as a critical signaling nexus for regulating 
      cellular metabolism, energy homeostasis, and cell growth. Thus, dysregulation of 
      this pathway contributes to the development of metabolic disorders such as 
      obesity, type 2diabetes, and cancer. We previously reported that a combination of 
      grape polyphenols (resveratrol, quercetin and catechin: RQC), at equimolar 
      concentrations, reduces breast cancer (BC) growth and metastasis in nude mice, 
      and inhibits Akt and mTOR activities and activates AMPK, an endogenous inhibitor 
      of mTOR, in metastatic BC cells. The objective of the present study was to 
      determine the contribution of individual polyphenols to the effect of combined 
      RQC on mTOR signaling. Metastatic BC cells were treated with RQC individually or 
      in combination, at various concentrations, and the activities (phosphorylation) 
      of AMPK, Akt, and the mTOR downstream effectors, p70S6 kinase (p70S6K) and 4E 
      binding protein (4EBP1), were determined by Western blot. Results show that 
      quercetin was the most effective compound for Akt/mTOR inhibition. Treatment with 
      quercetin at 15muM had a similar effect as the RQC combination in the inhibition 
      of BC cell proliferation, apoptosis, and migration. However, cell cycle analysis 
      showed that the RQC treatment arrested BC cells in the G1 phase, while quercetin 
      arrested the cell cycle in G2/M. In vivo experiments, using SCID mice with 
      implanted tumors from metastatic BC cells, demonstrated that administration of 
      quercetin at 15mg/kg body weight resulted in a ~70% reduction in tumor growth. In 
      conclusion, quercetin appears to be a viable grape polyphenol for future 
      development as an anti BC therapeutic.
FAU - Rivera Rivera, Amilcar
AU  - Rivera Rivera A
AD  - Department of Biochemistry, School of Medicine, University of Puerto Rico Medical 
      Sciences Campus, San Juan, Puerto Rico.
FAU - Castillo-Pichardo, Linette
AU  - Castillo-Pichardo L
AD  - Department of Biochemistry, School of Medicine, University of Puerto Rico Medical 
      Sciences Campus, San Juan, Puerto Rico.
AD  - Department of Pathology and Laboratory Medicine, Universidad Central del Caribe, 
      Bayamon, Puerto Rico.
FAU - Gerena, Yamil
AU  - Gerena Y
AD  - Department of Pharmacology and Toxicology, University of Puerto Rico Medical 
      Sciences Campus, San Juan, Puerto Rico.
FAU - Dharmawardhane, Suranganie
AU  - Dharmawardhane S
AD  - Department of Biochemistry, School of Medicine, University of Puerto Rico Medical 
      Sciences Campus, San Juan, Puerto Rico.
LA  - eng
GR  - P20 GM103475/GM/NIGMS NIH HHS/United States
GR  - U54 CA096297/CA/NCI NIH HHS/United States
GR  - G12 MD007583/MD/NIMHD NIH HHS/United States
GR  - R25 GM061838/GM/NIGMS NIH HHS/United States
GR  - G12 MD007600/MD/NIMHD NIH HHS/United States
GR  - SC3 GM084824/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20160610
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Stilbenes)
RN  - 8R1V1STN48 (Catechin)
RN  - 9IKM0I5T1E (Quercetin)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - Q369O8926L (Resveratrol)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Animals
MH  - Antineoplastic Agents, Phytogenic/chemistry/pharmacology/*therapeutic use
MH  - Breast/*drug effects/metabolism/pathology
MH  - Breast Neoplasms/*drug therapy/metabolism/pathology
MH  - Catechin/chemistry/pharmacology/*therapeutic use
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Female
MH  - Humans
MH  - Mice, Nude
MH  - Mice, SCID
MH  - Neoplasm Metastasis/pathology/prevention & control
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Quercetin/chemistry/pharmacology/*therapeutic use
MH  - Resveratrol
MH  - Signal Transduction/*drug effects
MH  - Stilbenes/chemistry/pharmacology/*therapeutic use
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Vitis/chemistry
PMC - PMC4902235
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2016/06/11 06:00
MHDA- 2017/07/19 06:00
PMCR- 2016/06/10
CRDT- 2016/06/11 06:00
PHST- 2016/01/19 00:00 [received]
PHST- 2016/05/26 00:00 [accepted]
PHST- 2016/06/11 06:00 [entrez]
PHST- 2016/06/11 06:00 [pubmed]
PHST- 2017/07/19 06:00 [medline]
PHST- 2016/06/10 00:00 [pmc-release]
AID - PONE-D-15-55547 [pii]
AID - 10.1371/journal.pone.0157251 [doi]
PST - epublish
SO  - PLoS One. 2016 Jun 10;11(6):e0157251. doi: 10.1371/journal.pone.0157251. 
      eCollection 2016.