Abstract 4177: Simultaneous activation of C-X-C chemokine receptor 4 and cannabinoid receptor 2 results in decreased angiogenesis

Abstract

Abstract Tumor angiogenesis is a complex process modulated by numerous signaling molecules and pathways that influence cell migration, invasion, survival and tube formation. The expression of the G-protein-coupled receptor (GPCR) C-X-C Chemokine Receptor 4 (CXCR4) has been correlated with the increased angiogenic potential of cancer cells. The ligand-specific binding of CXCL12 to CXCR4 increases tumor angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF) at both mRNA and protein levels. Thus, modulating the CXCR4/CXCL12 signaling axis provides an attractive target for the inhibition of tumor angiogenesis and cancer progression. Recent studies have suggested that in addition to its palliative properties, cannabis may have anti-proliferative and anti-metastatic effects by acting through the GPCR, cannabinoid receptor 2 (CB2R). GPCR heterodimerization has emerged as a means by which new signaling entities can be created with respect to agonist binding. Preliminary co-immunoprecipitation data from our lab indicates that agonist-bound CXCR4 and agonist-bound CB2R interact at the cell membrane and that receptor interaction mitigates the effects of CXCL12-mediated CXCR4 signaling. Here we show that co-stimulation of prostate cancer cells with CXCR4 and CB2R-specific agonists results in decreased VEGF expression in vitro. Furthermore, treatment of human endothelial cells with conditioned medium collected from co-stimulated prostate cancer cells decreased endothelial cell migration in wound healing and invasion assays, and decreased endothelial cell tubulogenesis. Taken together, these results demonstrate that desensitization of CXCR4 signaling through association with CB2R is a novel anti-angiogenic strategy and reinforces the clinical relevance of cannabinoids in cancer treatment. Note: This abstract was not presented at the meeting. Citation Format: Kisha A. Scarlett, Brittney Sandifer, Christopher J. Coke, Cimona V. Hinton. Simultaneous activation of C-X-C chemokine receptor 4 and cannabinoid receptor 2 results in decreased angiogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4177. doi:10.1158/1538-7445.AM2015-4177