Quercetin-6-C-β-D-glucopyranoside, natural analog of quercetin exhibits anti-prostate cancer activity by inhibiting Akt-mTOR pathway via aryl hydrocarbon receptor

Biochimie. 2015 Dec:119:68-79. doi: 10.1016/j.biochi.2015.10.012. Epub 2015 Oct 22.

Abstract

Pre-clinical studies suggest mitigating effect of dietary flavonoid quercetin against cancer and other diseases. However, quercetin suffers from poor metabolic stability, which appears to offset its pharmacological efficacy. Recently, we isolated quercetin-6-C-β-D-glucopyranoside (QCG) from Ulmus wallichiana planchon that has greater stability profile over quercetin. In the present study, the cytotoxic and apoptotic effects of QCG on prostate cancer cells were assessed. QCG inhibited prostate cancer cell proliferation by arresting cells at G0/G1 phase of cell cycle and induces apoptosis as evident from cytochrome c release, cleavage of caspase 3 and poly (ADP-ribose) polymerase. Mechanistic studies revealed that QCG inhibited reactive oxygen species (ROS) generation and Akt/mTOR cell survival pathways. Aryl hydrocarbon receptor (AhR) was a critical mediator of QCG action as knockdown of AhR attenuated QCG-induced cell cycle arrest, apoptosis and inhibition of Akt/mTOR pathway in prostate cancer cells. Taken together, our results suggest that QCG exhibits anti-cancer activity against prostate cancer cells via AhR-mediated down regulation of Akt/mTOR pathway in PC-3 cells.

Keywords: Akt/mTOR; Apoptosis; Aryl hydrocarbon receptor; Cell cycle; Prostate cancer; Quercetin-6-C-β-d-glucopyranoside (QCG).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / adverse effects
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / metabolism
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Basic Helix-Loop-Helix Transcription Factors / agonists*
  • Basic Helix-Loop-Helix Transcription Factors / chemistry
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Binding Sites
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Glucosides / adverse effects
  • Glucosides / chemistry
  • Glucosides / metabolism
  • Glucosides / pharmacology*
  • Humans
  • Ligands
  • Male
  • Molecular Docking Simulation
  • Neoplasm Proteins / agonists
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism
  • Prostate / drug effects
  • Prostate / metabolism
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quercetin / adverse effects
  • Quercetin / analogs & derivatives*
  • Quercetin / chemistry
  • Quercetin / metabolism
  • Quercetin / pharmacology
  • RNA Interference
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Receptors, Aryl Hydrocarbon / agonists*
  • Receptors, Aryl Hydrocarbon / chemistry
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism
  • Resting Phase, Cell Cycle / drug effects
  • Signal Transduction / drug effects*
  • Structural Homology, Protein
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • AHR protein, human
  • Antineoplastic Agents, Phytogenic
  • Basic Helix-Loop-Helix Transcription Factors
  • Glucosides
  • Ligands
  • Neoplasm Proteins
  • Reactive Oxygen Species
  • Receptors, Aryl Hydrocarbon
  • quercetin-6-C-beta-D-glucopyranoside
  • Quercetin
  • MTOR protein, human
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases