Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling

J Biol Chem. 2014 Aug 8;289(32):21960-72. doi: 10.1074/jbc.M114.561761. Epub 2014 Jun 18.

Abstract

The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. Because a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells. Here we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo. These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology.

Keywords: Cancer; Cannabinoid; Cannabinoid Receptor; G Protein-coupled Receptor (GPCR); Signal Transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cannabinoids / metabolism
  • Cannabinoids / pharmacology
  • Cell Line, Tumor
  • Dronabinol / pharmacology
  • Female
  • Gene Targeting
  • Glioblastoma / drug therapy
  • Glioblastoma / genetics
  • Glioblastoma / metabolism
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Protein Structure, Quaternary
  • RNA, Small Interfering / genetics
  • Receptor, Cannabinoid, CB2 / chemistry*
  • Receptor, Cannabinoid, CB2 / genetics
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Receptors, Cannabinoid
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • CNR2 protein, human
  • Cannabinoids
  • GPR55 protein, human
  • RNA, Small Interfering
  • Receptor, Cannabinoid, CB2
  • Receptors, Cannabinoid
  • Receptors, G-Protein-Coupled
  • Recombinant Proteins
  • Dronabinol