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.

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer

“…A recent study revealed that ADRB2 agonists downregulated the MYC pathway and HIF-1A, inducing specific metabolic reprogramming in PDAC (40). These reprogramming include the upregulation of glycolytic metabolism and changes in acylcarnitine levels (40), ultimately leading to the suppression of PDAC progression. These findings parallel our observations regarding ADRA2A in this study.…”

“…Adrenoceptor beta 2 (ADRB2) is a member of adrenergic receptor family, sharing similar functions with ADRA2A. A recent study revealed that ADRB2 agonists downregulated the MYC pathway and HIF-1A, inducing specific metabolic reprogramming in PDAC (40). These reprogramming include the upregulation of glycolytic metabolism and changes in acylcarnitine levels (40), ultimately leading to the suppression of PDAC progression.…”

Obesity and cancer—extracellular matrix, angiogenesis, and adrenergic signaling as unusual suspects linking the two diseases

“…1 ). Only subsets of patients will progress along the sequence of worsened pathophysiological states from NAFL to NASH and further to cirrhosis, thereby being exposed to an increasing risk for HCC development [ 246 ]. The pathophysiological mechanisms underlying the risk connection between NAFLD and HCC include various components such as immune and inflammatory responses, DNA damage, oxidative stress, changes in the microbiome, and others that go beyond the scope of this review and have been comprehensively summarized elsewhere [ 5 ].…”