title: Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveals a Mechanism for Regulation of Tumor Progression.
abstract: The G-protein-coupled chemokine receptor CXCR4 generates signals that lead to cell migration, cell proliferation, and other survival mechanisms that result in the metastatic spread of primary tumor cells to distal organs. Numerous studies have demonstrated that CXCR4 can form homodimers or can heterodimerize with other G-protein-coupled receptors to form receptor complexes that can amplify or decrease the signaling capacity of each individual receptor. Using biophysical and biochemical approaches, we found that CXCR4 can form an induced heterodimer with cannabinoid receptor 2 (CB2) in human breast and prostate cancer cells. Simultaneous, agonist-dependent activation of CXCR4 and CB2 resulted in reduced CXCR4-mediated expression of phosphorylated ERK1/2 and ultimately reduced cancer cell functions such as calcium mobilization and cellular chemotaxis. Given that treatment with cannabinoids has been shown to reduce invasiveness of cancer cells as well as CXCR4-mediated migration of immune cells, it is plausible that CXCR4 signaling can be silenced through a physical heterodimeric association with CB2, thereby inhibiting subsequent functions of CXCR4. Taken together, the data illustrate a mechanism by which the cannabinoid system can negatively modulate CXCR4 receptor function and perhaps tumor progression.
authors: From the Department of Biological Sciences and the Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia 30314.
authors: Christopher J
authors: CJ
authors: Coke
authors: From the Department of Biological Sciences and the Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia 30314.
authors: Kisha A
authors: KA
authors: Scarlett
authors: Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C. 20057, and.
authors: Mahandranauth A
authors: MA
authors: Chetram
authors: From the Department of Biological Sciences and the Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia 30314.
authors: Kia J
authors: KJ
authors: Jones
authors: From the Department of Biological Sciences and the Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia 30314.
authors: Brittney J
authors: BJ
authors: Sandifer
authors: From the Department of Biological Sciences and the Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia 30314.
authors: Ahriea S
authors: AS
authors: Davis
authors: Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia 30322.
authors: Adam I
authors: AI
authors: Marcus
authors: From the Department of Biological Sciences and the Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia 30314, chinton@cau.edu.
authors: Cimona V
authors: http://orcid.org/0000-0002-5724-1804
authors: CV
authors: Hinton
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002186:Cannabinoids / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D055503:Protein Multimerization; D043885:Receptor, Cannabinoid, CB2 / Q000737:chemistry* / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000737:chemistry* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D002186:Cannabinoids; D043885:Receptor, Cannabinoid, CB2; D019718:Receptors, CXCR4
keywords: CXC chemokine receptor type 4 (CXCR-4); G protein-coupled receptor (GPCR); cannabinoid receptor; dimerization; metastasis