title: Resveratrol enhances the anti-tumor activity of the mTOR inhibitor rapamycin in multiple breast cancer cell lines mainly by suppressing rapamycin-induced AKT signaling.
abstract: The anti-tumor activity of rapamycin is compromised by the feedback-loop-relevant hyperactive PI3K and ERK-MAPK pathway signaling. In breast cancer cells treated with rapamycin, we observed a moderate increase of AKT phosphorylation (P-AKT) in a rapamycin resistant cell line, MDA-MB-231, as well as a slight increase of P-AKT in a rapamycin sensitive cell line, MCF-7. We found that resveratrol, a natural phytoalexin, suppressed the phosphorylation and activation of the PI3K/AKT pathway in all the three breast cancer cell lines that we tested. It also had a weak inhibitory effect on the activation of the mTOR/p70S6K pathway in two cell lines expressing wildtype PTEN, MCF-7 and MDA-MB-231. The combined use of resveratrol and rapamycin resulted in modest additive inhibitory effects on the growth of breast cancer cells, mainly through suppressing rapamycin-induced AKT activation. We, therefore, reveal a novel combination whereby resveratrol potentiates the growth inhibitory effect of rapamycin, with the added benefit of preventing eventual resistance to rapamycin, likely by suppressing AKT signaling. We also present data herein that PTEN is an important contributor to resveratrol's growth suppressive effects and its potentiation of rapamycin in this therapeutic scenario, as resveratrol's suppression of rapamycin-mediated induction of P-AKT is both PTEN-dependent and -independent. Thus, the resveratrol-rapamycin combination may have therapeutic value in treating breast cancer and perhaps other processes where mTOR is activated.
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, OH 44195, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Jinhong
authors.initials: J
authors.lastname: Zhu
authors.forename: Mohammed
authors.initials: M
authors.lastname: Orloff
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D020128:Inhibitory Concentration 50; D008565:Membrane Proteins / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077185:Resveratrol; D020123:Sirolimus; D013267:Stilbenes; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C446603:TPTE protein, human