Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveals a Mechanism for Regulation of Tumor Progression

• Type of Material: Article
• Authors: Christopher J. Coke, Clark Atlanta University; Kisha A. Scarlett, Clark Atlanta University; Mahandranauth A. Chetram, Georgetown University; Kia J. Jones, Clark Atlanta University; Brittney J. Sandifer, Clark Atlanta University; Ahriea S. Davis, Clark Atlanta University; Adam Marcus, Emory University; Cimona V. Hinton, Clark Atlanta University
• Language: English
• Date: 2016-05-06
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M115.712661
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 291
• Issue: 19
• Start Page: 9991
• End Page: 10005
• Grant/Funding Information: This work was supported by National Institutes of Health Grants 1R01GM106020, 3R01GM106020, and R25GM060414 from the NIGMS and Grant 5G12MD007590 from the Research Centers in Minority Institutions Program.
• Keywords: Biochemistry & Molecular Biology; PROTEIN-COUPLED RECEPTORS; BREAST-CANCER; T-LYMPHOCYTES; DELTA-OPIOID RECEPTORS; ENDOTHELIAL-CELLS; IMMUNE-RESPONSE; Science & Technology; ADENYLATE-CYCLASE; SIGNALING PATHWAYS; Life Sciences & Biomedicine; PROSTATE-CANCER CELLS; LEUKOCYTE ACTIVATION
• Research Categories: Health Sciences, Oncology

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, agonistdependent 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.