Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β2 adrenergic agonist
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Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β2 adrenergic agonist. / Wnorowski, Artur; Dudzik, Danuta; Bernier, Michel; Wójcik, Jakub; Keijzers, Guido; Diaz-Ruiz, Alberto; Mazur, Karolina; Zhang, Yongqing; Han, Haiyong; Scheibye-Knudsen, Morten; Jozwiak, Krzysztof; Barbas, Coral; Wainer, Irving W.
I: Scientific Reports, Bind 12, Nr. 1, 3618, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β2 adrenergic agonist
AU - Wnorowski, Artur
AU - Dudzik, Danuta
AU - Bernier, Michel
AU - Wójcik, Jakub
AU - Keijzers, Guido
AU - Diaz-Ruiz, Alberto
AU - Mazur, Karolina
AU - Zhang, Yongqing
AU - Han, Haiyong
AU - Scheibye-Knudsen, Morten
AU - Jozwiak, Krzysztof
AU - Barbas, Coral
AU - Wainer, Irving W.
N1 - Publisher Copyright: © 2022, The Author(s).
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1038/s41598-022-07600-x
DO - 10.1038/s41598-022-07600-x
M3 - Journal article
C2 - 35256673
AN - SCOPUS:85125969391
VL - 12
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 3618
ER -
ID: 305697503