Resveratrol directly targets DDX5 resulting in suppression of the mTORC1 pathway in prostate cancer

Cell Death Dis. 2016 May 5;7(5):e2211. doi: 10.1038/cddis.2016.114.

Abstract

Resveratrol has various attractive bioactivities, such as prevention of cancer, neurodegenerative disorders, and obesity-related diseases. Therefore, identifying its direct binding proteins is expected to discover druggable targets. Sirtuin 1 and phosphodiesterases have so far been found as the direct molecular targets of resveratrol. We herein identified 11 novel resveratrol-binding proteins, including the DEAD (Asp-Glu-Ala-Asp) box helicase 5 (DDX5, also known as p68), using resveratrol-immobilized beads. Treatment with resveratrol induced degradation of DDX5 in prostate cancer cells. Depletion of DDX5 caused apoptosis by inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. Moreover, knockdown of DDX5 attenuated the inhibitory activities of resveratrol against mTORC1 signaling and cancer cell growth. These data show that resveratrol directly targets DDX5 and induces cancer cell death by inhibiting the mTORC1 pathway.

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Antioxidants / pharmacology*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • DEAD-box RNA Helicases / antagonists & inhibitors*
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Dose-Response Relationship, Drug
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Molecular Targeted Therapy
  • Multiprotein Complexes / antagonists & inhibitors*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Prostate / drug effects
  • Prostate / metabolism
  • Prostate / pathology
  • Proteolysis / drug effects
  • Resveratrol
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction
  • Stilbenes / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents, Phytogenic
  • Antioxidants
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Multiprotein Complexes
  • Phosphoproteins
  • Stilbenes
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Ddx5 protein, human
  • DEAD-box RNA Helicases
  • Resveratrol