Abstract 4989: Cannabinoid receptor 2 and C-X-C chemokine receptor 4 interact to abrogate CXCL12-mediated cellular response

Abstract

Abstract The expression of C-X-C Chemokine Receptor 4 (CXCR4) has been correlated with increased metastatic potential of cancer cells. CXCR4 increases tumor malignancy by encouraging tumors cells to migrate to distal organs expressing its cognate ligand, CXCL12, facilitating metastasis. Thus, targeting the CXCR4/CXCL12 signaling axis provides a good strategy to inhibit the metastatic spread of tumor cells and slow cancer progression. Recent studies suggest that cannabis may have anti-proliferative as well as anti-metastatic properties, though a biochemical mechanism describing how this occurs has yet to be discovered. Our lab has confirmed that an interaction between agonist-bound CXCR4 and agonist-bound Cannabinoid Receptor 2 (CB2) can decrease cancer cell migration. Simultaneous treatment of the breast cancer cell line, MDA-MB-231 with CXCL12 and AM1241, a synthetic ligand for CB2, desensitized the intrinsic cellular response to migrate toward areas of high CXCL12 concentration. Furthermore, through co-immunoprecipitation, we determined that there was increased interaction between the two receptors with co-stimulation. When CXCR4 and CB2 were activated simultaneously with various agonists, decreases in migration were observed, confirming that the regulatory activity was receptor-based, not agonist-based. Moreover, when cells were treated with the CB2 antagonist (AM630) and CXCL12 simultaneously, the decrease in migration was no longer seen, as CXCL12 was able to induce cell movement. In order to determine whether receptors were activated in response to simultaneous stimulation, calcium mobilization assays were performed and results showed that transiently activated calcium levels were significantly lower in response to simultaneous treated cells when compared to cells treat with their individual ligands. Therefore, we propose that the interaction of CB2 with CXCR4 may play a role in inhibiting the cells response to CXCL12, leading to a loss in metastatic potential and presenting a new mechanism for regulating oncogenic signaling. Citation Format: Christopher Coke, Ahriea Johnson, Kia Jones, Cimona Hinton. Cannabinoid receptor 2 and C-X-C chemokine receptor 4 interact to abrogate CXCL12-mediated cellular response. [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 4989. doi:10.1158/1538-7445.AM2015-4989