Cannabinoid Type 2 Receptors Promote Cadherin Switching While Suppressing Cell Migration: A Novel Investigation into Biased GPCR Signaling
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Authors
Aldbai, Rachil
Date
2025-06-23
Type
thesis
Language
eng
Keyword
Cannabinoid Type 2 Receptor , Metastasis , Pancreatic cancer , Biased agonism
Alternative Title
Abstract
The role of cannabinoid receptor type 2 (CB2) in cancer remains enigmatic, with emerging evidence suggesting a dual tumor-suppressive and tumor-promoting role, depending on the context. Current literature highlights that the paradoxical role of the G protein-coupled receptor (GPCR) CB2 may result from pathway-selective signaling, contingent upon the diverse cancer-related signaling modulated by cannabinoid receptors. Nonetheless, the precise mechanism(s) by which CB2 regulates gene expression involved in cancer development and progression remain largely unexplored. Recently, studies revealed a novel GPCR signaling paradigm involving heteromer formation between GPCRs and the neuromedin B receptor (NMBR), in complex with neuraminidase 1 (Neu1) and matrix metalloproteinase 9 (MMP9). This crosstalk facilitated the glycosylated receptor activation and downstream gene regulation mediated by nuclear factor kappa B (NF-κB). Importantly, cannabinoid type 1 (CB1) receptors have been implicated in this novel biased signaling pathway. Therefore, the present study aimed to investigate whether CB2 GPCRs are similarly involved in the proposed signaling paradigm to induce epithelial-mesenchymal transition (EMT) and a metastatic phenotype.
Synthetic CB2 agonists, JWH-133, SER-601, and HU-308, significantly induce Neu1 sialidase activity in a dose-dependent fashion in RAW-Blue (murine macrophages) and PANC-1 (pancreatic) cells, as assessed by live-cell sialidase assay. This activity was abrogated by selective inhibitors of NMBR (BIM-23127), MMP9 (MMP9-i), and Neu1 (oseltamivir phosphate; OP), suggesting pathway specificity. Colocalization analyses further revealed that CB2 receptors form heteromeric complexes with Neu1 in naïve, unstimulated PANC-1 cells, indicating a molecular interaction at the cell surface. We further assessed NF-κB-dependent secretory alkaline phosphatase (SEAP) reporter assay and found that synthetic CB2 agonists significantly upregulate NF-κB activity. This may contribute to the observed downregulation of E-cadherin and upregulation of N-cadherin in PANC-1 cells, as determined by immunofluorescence. Interestingly, in a scratch wound assay, synthetic CB2 cannabinoids significantly reduce the migratory capacity of PANC-1 cells.
The current findings suggest that CB2-mediated effects may stem from biased agonism and allosteric modulation within the CB2 GPCR, rather than differences in ligand efficacy or stimulus-response coupling. Elucidating the strength and kinetic profile of CB2 agonists in this signaling platform may yield crucial insights into cannabinoid potential as therapeutic agents in cancer.
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Attribution-NonCommercial-NoDerivatives 4.0 International