Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased ß2 adrenergic agonist.

Metabolic reprogramming contributes to oncogenesis, tumor growth, and treatment resistance in pancreatic ductal adenocarcinoma (PDAC). Here we report the effects of (R,S')-4'-methoxy-1-naphthylfenoterol (MNF), a GPR55 antagonist and biased ß2-adrenergic receptor (ß2-AR) agonist on cellular signaling implicated in proliferation and metabolism in PDAC cells. The relative contribution of GPR55 and ß2-AR in (R,S')-MNF signaling was explored further in PANC-1 cells. Moreover, the effect of (R,S')-MNF on tumor growth was determined in a PANC-1 mouse xenograft model. PANC-1 cells treated with (R,S')-MNF showed marked attenuation in GPR55 signal transduction and function combined with increased ß2-AR/Gαs/adenylyl cyclase/PKA signaling, both of which contributing to lower MEK/ERK, PI3K/AKT and YAP/TAZ signaling. (R,S')-MNF administration significantly reduced PANC-1 tumor growth and circulating L-lactate concentrations. Global metabolic profiling of (R,S')-MNF-treated tumor tissues revealed decreased glycolytic metabolism, with a shift towards normoxic processes, attenuated glutamate metabolism, and increased levels of ophthalmic acid and its precursor, 2-aminobutyric acid, indicative of elevated oxidative stress. Transcriptomics and immunoblot analyses indicated the downregulation of gene and protein expression of HIF-1α and c-Myc, key initiators of metabolic reprogramming in PDAC. (R,S')-MNF treatment decreased HIF-1α and c-Myc expression, attenuated glycolysis, shifted fatty acid metabolism towards ß-oxidation, and suppressed de novo pyrimidine biosynthesis in PANC-1 tumors. The results indicate a potential benefit of combined GPR55 antagonism and biased ß2-AR agonism in PDAC therapy associated with the deprogramming of altered cellular metabolism.

Gene Expression Data Mining Reveals the Involvement of GPR55 and Its Endogenous Ligands in Immune Response, Cancer, and Differentiation.

G protein-coupled receptor 55 (GPR55) is a recently deorphanized lipid- and peptide-sensing receptor. Its lipidic endogenous agonists belong to lysoglycerophospholipids, with lysophosphatidylinositol (LPI) being the most studied. Peptide agonists derive from fragmentation of pituitary adenylate cyclase-activating polypeptide (PACAP). Although GPR55 and its ligands were implicated in several physiological and pathological conditions, their biological function remains unclear. Thus, the aim of the study was to conduct a large-scale re-analysis of publicly available gene expression datasets to identify physiological and pathological conditions affecting the expression of GPR55 and the production of its ligands. The study revealed that regulation of GPR55 occurs predominantly in the context of immune activation pointing towards the role of the receptor in response to pathogens and in immune cell lineage determination. Additionally, it was revealed that there is almost no overlap between the experimental conditions affecting the expression of GPR55 and those modulating agonist production. The capacity to synthesize LPI was enhanced in various types of tumors, indicating that cancer cells can hijack the motility-related activity of GPR55 to increase aggressiveness. Conditions favoring accumulation of PACAP-derived peptides were different than those for LPI and were mainly related to differentiation. This indicates a different function of the two agonist classes and possibly the existence of a signaling bias.