GPR55 receptor antagonist decreases glycolytic activity in PANC-1 pancreatic cancer cell line and tumor xenografts

Michel Bernier, Jonathan Catazaro, Nagendra S. Singh, Artur Wnorowski, Anna Boguszewska-Czubara, Krzysztof Jozwiak, Robert Powers, Irving W. Wainer

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The Warburg effect is a predominant metabolic pathway in cancer cells characterized by enhanced glucose uptake and its conversion to l-lactate and is associated with upregulated expression of HIF-1α and activation of the EGFR-MEK-ERK, Wnt-β-catenin, and PI3K-AKT signaling pathways. (R,R′)-4′-methoxy-1-naphthylfenoterol ((R,R′)-MNF) significantly reduces proliferation, survival, and motility of PANC-1 pancreatic cancer cells through inhibition of the GPR55 receptor. We examined (R,R′)-MNF's effect on glycolysis in PANC-1 cells and tumors. Global NMR metabolomics was used to elucidate differences in the metabolome between untreated and (R,R′)-MNF-treated cells. LC/MS analysis was used to quantify intracellular concentrations of β-hydroxybutyrate, carnitine, and l-lactate. Changes in target protein expression were determined by Western blot analysis. Data was also obtained from mouse PANC-1 tumor xenografts after administration of (R,R′)-MNF. Metabolomics data indicate that (R,R′)-MNF altered fatty acid metabolism, energy metabolism, and amino acid metabolism and increased intracellular concentrations of β-hydroxybutyrate and carnitine while reducing l-lactate content. The cellular content of phosphoinositide-dependent kinase-1 and hexokinase 2 was reduced consistent with diminished PI3K-AKT signaling and glucose metabolism. The presence of the GLUT8 transporter was established and found to be attenuated by (R,R′)-MNF. Mice treated with (R,R′)-MNF had significant accumulation of l-lactate in tumor tissue relative to vehicle-treated mice, together with reduced levels of the selective l-lactate transporter MCT4. Lower intratumoral levels of EGFR, pyruvate kinase M2, β-catenin, hexokinase 2, and p-glycoprotein were also observed. The data suggest that (R,R′)-MNF reduces glycolysis in PANC-1 cells and tumors through reduced expression and function at multiple controlling sites in the glycolytic pathway.

Original languageEnglish (US)
Pages (from-to)2131-2142
Number of pages12
JournalInternational Journal of Cancer
Volume141
Issue number10
DOIs
StatePublished - Nov 15 2017

Keywords

  • PKM2
  • Warburg effect
  • l-lactate
  • metabolic reprogramming
  • metabolomics
  • pancreatic cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Bernier, M., Catazaro, J., Singh, N. S., Wnorowski, A., Boguszewska-Czubara, A., Jozwiak, K., Powers, R., & Wainer, I. W. (2017). GPR55 receptor antagonist decreases glycolytic activity in PANC-1 pancreatic cancer cell line and tumor xenografts. International Journal of Cancer, 141(10), 2131-2142. https://doi.org/10.1002/ijc.30904