Anti-Breast Cancer Potential of Quercetin via the Akt/AMPK/Mammalian Target of Rapamycin (mTOR) Signaling Cascade.
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 15μM 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.
Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Amilcar
A
Rivera Rivera
Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.|Department of Pathology and Laboratory Medicine, Universidad Central del Caribe, Bayamón, Puerto Rico.
Linette
L
Castillo-Pichardo
Department of Pharmacology and Toxicology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Yamil
Y
Gerena
Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Suranganie
S
Dharmawardhane
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002392:Catechin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D008819:Mice, Nude; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D027843:Vitis / Q000737:chemistry
D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D002392:Catechin; D011794:Quercetin; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol