Cargando…
Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β(2) 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 β(2)-adrenergic receptor (β(2)-AR) agonist on cellular signa...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8901637/ https://www.ncbi.nlm.nih.gov/pubmed/35256673 http://dx.doi.org/10.1038/s41598-022-07600-x |
_version_ | 1784664409135644672 |
---|---|
author | 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. |
author_facet | 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. |
author_sort | Wnorowski, Artur |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8901637 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-89016372022-03-08 Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β(2) 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. Sci Rep Article 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. Nature Publishing Group UK 2022-03-07 /pmc/articles/PMC8901637/ /pubmed/35256673 http://dx.doi.org/10.1038/s41598-022-07600-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article 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. Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β(2) adrenergic agonist |
title | Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β(2) adrenergic agonist |
title_full | Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β(2) adrenergic agonist |
title_fullStr | Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β(2) adrenergic agonist |
title_full_unstemmed | Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β(2) adrenergic agonist |
title_short | Deprogramming metabolism in pancreatic cancer with a bi-functional GPR55 inhibitor and biased β(2) adrenergic agonist |
title_sort | deprogramming metabolism in pancreatic cancer with a bi-functional gpr55 inhibitor and biased β(2) adrenergic agonist |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8901637/ https://www.ncbi.nlm.nih.gov/pubmed/35256673 http://dx.doi.org/10.1038/s41598-022-07600-x |
work_keys_str_mv | AT wnorowskiartur deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist AT dudzikdanuta deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist AT berniermichel deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist AT wojcikjakub deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist AT keijzersguido deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist AT diazruizalberto deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist AT mazurkarolina deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist AT zhangyongqing deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist AT hanhaiyong deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist AT scheibyeknudsenmorten deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist AT jozwiakkrzysztof deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist AT barbascoral deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist AT wainerirvingw deprogrammingmetabolisminpancreaticcancerwithabifunctionalgpr55inhibitorandbiasedb2adrenergicagonist |