Journal Article

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

Wnorowski, Artur, Mazur, Karolina, Bernier, Michel, Han, Haiyong, Wójcik, Jakub, Scheibye-Knudsen, Morten, Barbas, Coral, Keijzers, Guido, Dudzik, Danuta, Jozwiak, Krzysztof, Diaz-Ruiz, Alberto, Zhang, Yongqing, Wainer, Irving W.

2022

Overview

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 β 2 -adrenergic receptor (β 2 -AR) agonist on cellular signaling implicated in proliferation and metabolism in PDAC cells. The relative contribution of GPR55 and β 2 -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 β 2 -AR/Gα s /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 β 2 -AR agonism in PDAC therapy associated with the deprogramming of altered cellular metabolism.

• Publisher: Nature Publishing Group UK,Nature Portfolio
• Subject: 631/154/436/2387 / 631/45/320 / 631/67/1504/1713 / 631/67/2327 / Humanities and Social Sciences / multidisciplinary / Science / Science (multidisciplinary)