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Simple Summary: Our recent findings unveil a potential game-changer in cancer therapy. We have discovered that synthetic CB1 cannabinoids, specifically AM-404, arvanil, and olvanil, can surreptitiously orchestrate tunneling nanotubes, enhance cell viability, and promote scratch wound migration and epithelial–mesenchymal transition (EMT) in pancreatic PANC-1 and colorectal SW-620 cancer cells. Metastasizing cancer cells surreptitiously can adapt to metabolic activity during their invasion. By initiating their communications for invasion, cancer cells can reprogram their cellular activities to initiate their proliferation and migration and uniquely counteract metabolic stress during their progression. During this reprogramming process, cancer cells' metabolism and other cellular activities are integrated and mutually regulated by tunneling nanotube communications to alter their specific metabolic functional drivers of tumor growth and progression. Here, we investigated the in vitro effects of the synthetic CB1 cannabinoids AM-404, arvanil, and olvanil on human pancreatic PANC-1 and colorectal SW-620 cancer cell lines to understand further cellular behaviors and the potential risks of their use in cancer therapy. For the first time, the synthetic CB1 cannabinoids AM-404, arvanil, and olvanil significantly altered cancer cells in forming missile-like shapes to induce tunneling nanotube (TNT) communications in PANC-1 cells. Oseltamivir phosphate (OP) significantly prevented TNT formation. To assess the key survival pathways critical for pancreatic cancer progression, we used the AlamarBlue assay to determine synthetic CB1 cannabinoids to induce the cell's metabolic viability drivers to stage migratory intercellular communication. The synthetic CB1 cannabinoids significantly increased cell viability compared to the untreated control for PANC-1 and SW-620 cells, and this response was significantly reduced with the NMBR inhibitor BIM-23127, neuraminidase-1 inhibitor OP, and MMP-9 inhibitor (MMP-9i). CB1 cannabinoids also significantly increased N-cadherin and decreased E-cadherin EMT markers compared to the untreated controls, inducing the process of metastatic phenotype for invasion. BIM-23127, MMP9i, and OP significantly inhibited CB1 agonist-induced NFκB-dependent secretory alkaline phosphatase (SEAP) activity. To confirm this concept, we investigated the migratory invasiveness of PANC-1 and SW-620 cancer cells treated with the synthetic CB1 cannabinoids AM-404, arvanil, and olvanil in a scratch wound assay. CB1 cannabinoids significantly induced the rate of migration and invasiveness of PANC-1 cancer cells, whereas they had minimal effect on the rate of migration of already metastatic SW-620 cancer cells. Interestingly, olvanil-treated SW-620 cells significantly enhanced the migration rate and invasiveness of these cells. The data support the cellular and molecular mechanisms of the synthetic CB1 cannabinoids, orchestrating intercellular conduits to enhance metabolic drivers to stage migratory intercellular communication in pancreatic cancer cells. [ABSTRACT FROM AUTHOR]

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Simple Summary: Non-nutritive sweeteners (NNS) are widely used by individuals to lower their caloric intake, lose weight, and sustain a healthy diet. The specific mechanistic details of the effects of NNS consumption by individuals on host metabolism and energy homeostasis are unknown. This topic is highly relevant as NNS has been promoted as an option to improve health. However, NNS consumption has been associated with increased risk factors for metabolic syndrome (MetSyn), resulting in diseases like cardiovascular dysfunction, type 2 diabetes mellitus (T2DM), cancer, and metastasis. This report presents a novel molecular mechanism of how NNS and natural sugars binding taste receptors transmogrify glycosylated receptors on cancer cells to induce the epithelial-mesenchymal transition of the metastatic phenotype. Understanding the role of biased taste T1R2/T1R3 G protein-coupled receptors (GPCR) agonists on glycosylated receptor signaling may provide insights into the opposing effects mediated by artificial and natural sweeteners, particularly in cancer and metastasis. Sweetener-taste GPCRs can be activated by several active states involving either biased agonism, functional selectivity, or ligand-directed signaling. However, there are increasing arrays of sweetener ligands with different degrees of allosteric biased modulation that can vary dramatically in binding- and signaling-specific manners. Here, emerging evidence proposes the involvement of taste GPCRs in a biased GPCR signaling crosstalk involving matrix metalloproteinase-9 (MMP-9) and neuraminidase-1 (Neu-1) activating glycosylated receptors by modifying sialic acids. The findings revealed that most natural and artificial sweeteners significantly activate Neu-1 sialidase in a dose-dependent fashion in RAW-Blue and PANC-1 cells. To confirm this biased GPCR signaling crosstalk, BIM-23127 (neuromedin B receptor inhibitor, MMP-9i (specific MMP-9 inhibitor), and oseltamivir phosphate (specific Neu-1 inhibitor) significantly block sweetener agonist-induced Neu-1 sialidase activity. To assess the effect of artificial and natural sweeteners on the key survival pathways critical for pancreatic cancer progression, we analyzed the expression of epithelial-mesenchymal markers, CD24, ADLH-1, E-cadherin, and N-cadherin in PANC-1 cells, and assess the cellular migration invasiveness in a scratch wound closure assay, and the tunneling nanotubes (TNTs) in staging the migratory intercellular communication. The artificial and natural sweeteners induced metastatic phenotype of PANC-1 pancreatic cancer cells to promote migratory intercellular communication and invasion. The sweeteners also induced the downstream NFκB activation using the secretory alkaline phosphatase (SEAP) assay. These findings elucidate a novel taste T1R2/T1R3 GPCR functional selectivity of a signaling platform in which sweeteners activate downstream signaling, contributing to tumorigenesis and metastasis via a proposed NFκB-induced epigenetic reprogramming modeling. [ABSTRACT FROM AUTHOR]

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 more than one active state, a phenomenon called either '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 GPCRs in a novel biased GPCR signaling paradigm involving the crosstalk between neuraminidase-1 (Neu-1) and matrix metalloproteinase-9 (MMP-9) in the activation of glycosylated receptors through the modification of the receptor glycosylation state. The study findings highlighted the role of CB1 agonists AM-404, Aravnil, and Olvanil in significantly inducing Neu-1 sialidase activity in a dose-dependent fashion in RAW-Blue, PANC-1, and SW-620 cells. This approach was further substantiated by findings that the neuromedin B receptor inhibitor, BIM-23127, MMP-9 inhibitor, MMP9i, 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 that regulates the interaction and signaling mechanism among these molecules present on the cell surface. Moreover, the study results demonstrate that CB1 agonists induce NFκB-dependent secretory alkaline phosphatase (SEAP) activity in influencing the expression of epithelial–mesenchymal markers, E-cadherin, and vimentin in SW-620 cells, albeit the impact on E-cadherin expression is less pronounced compared to vimentin. 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. [ABSTRACT FROM AUTHOR]