Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β2 adrenergic agonist.

Abstract

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 β2-adrenergic receptor (β2-AR) agonist on cellular signaling implicated in proliferation and metabolism in PDAC cells. The relative contribution of GPR55 and β2-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 β2-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 β-oxidation, and suppressed de novo pyrimidine biosynthesis in PANC-1 tumors. The results indicate a potential benefit of combined GPR55 antagonism and biased β2-AR agonism in PDAC therapy associated with the deprogramming of altered cellular metabolism.

• Authors: Artur Wnorowski, Danuta Dudzik, Michel Bernier, Jakub Wójcik, Guido Keijzers, Alberto Diaz-Ruiz, Karolina Mazur, Yongqing Zhang, Haiyong Han, Morten Scheibye-Knudsen, Krzysztof Jozwiak, Coral Barbas, Irving W Wainer
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 3618 (03 07 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35256673 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Adrenergic Agonists
• GPR55 protein, human
• GPR55 protein, mouse
• Receptors, Adrenergic, beta-2
• Receptors, Cannabinoid
• Fenoterol

Topics

• Adrenergic Agonists (pharmacology)
• Animals
• Cell Line, Tumor
• Cell Proliferation
• Fenoterol (pharmacology)
• Humans
• Mice
• Pancreatic Neoplasms (pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Receptors, Adrenergic, beta-2 (metabolism)
• Receptors, Cannabinoid (metabolism)
• Signal Transduction