Exploring The Functional Selectivity Of Cannabinoid Type 1 G Protein-Coupled Receptor Agonists In Pancreatic and Colorectal Cancer

Abstract

Understanding the role of biased G protein-coupled receptor (GPCR) agonism in receptor signaling may provide novel insights into the opposing effects mediated by cannabinoids, particularly in cancer and cancer metastasis. GPCRs can have multiple active states, a phenomenon called ‘biased agonism,’ ‘functional selectivity,’ or ‘ligand-directed signaling.’ However, there are increasing arrays of cannabinoid allosteric ligands with different degrees of modulation, called ‘biased modulation,’ that can vary dramatically in a probe- and pathway-specific manner, not from simple differences in orthosteric ligand efficacy or stimulus-response coupling. Here, emerging evidence proposes the involvement of CB1 (Cannabinoid receptor 1) GPCRs in a novel biased GPCR signaling paradigm involving the crosstalk between Neuromedin-B (NMBR) neuraminidase-1 (Neu-1) and matrix-metalloproteinase-9 (MMP-9) in the activation of the glycosylated receptors through the modification of the receptor glycosylation state. The study findings highlighted the role of CB1 agonists AM-404, Arvanil, and Olvanil in significantly inducing Neu-1 sialidase activity in a dose-dependent fashion in RAW-Blue (murine macrophages), PANC-1 (pancreatic), and SW-620 (colorectal) cells. This approach was further substantiated by findings that the neuromedin B receptor inhibitor, BIM-23127, MMP-9 inhibitor, MMP-9i, and Neu-1 inhibitor, oseltamivir phosphate, could specifically block CB1 agonist-induced Neu-1 sialidase activity. Additionally, we found that CB1 receptors exist in a multimeric receptor complex with Neu-1 in naïve, unstimulated RAW-Blue, PANC-1, and SW-620 cells. This complex implies a molecular link regulating the interaction and signaling mechanism among these molecules on the cell surface. We found that treating these cells with the synthetic cannabinoids also increased cell viability, migration, and cellular projections in PANC-1 cells. However, migration was not increased in SW-620 cells, except for Olvanil. Moreover, the study results demonstrate that CB1 agonists induce NF-κB-dependent secretory alkaline phosphatase (SEAP) activity in influencing the expression of epithelial-mesenchymal markers, E-cadherin, and N-Cadherin in PANC-1 cells and vimentin in SW-620 cells. In essence, this innovative research begins to elucidate an entirely new molecular mechanism involving a GPCR signaling paradigm in which cannabinoids, as epigenetic stimuli, may traverse to influence gene expression and contribute to cancer and cancer metastasis.