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Int J Cancer. 2017 Nov 15;141(10):2131-2142. doi: 10.1002/ijc.30904. Epub 2017 Aug 7.

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

Author information

1
Translational Gerontology Branch, Intramural Research Program of the National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224.
2
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588-0304.
3
Laboratory of Clinical Investigation, Intramural Research Program of the National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224.
4
Department of Biopharmacy, Medical University of Lublin, Lublin, 20-093, Poland.
5
Department of Medical Chemistry, Medical University of Lublin, Lublin, 20-093, Poland.
6
Mitchell Woods Pharmaceuticals, Shelton, CT, 06484.

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.

KEYWORDS:

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

PMID:
28741686
PMCID:
PMC6028007
DOI:
10.1002/ijc.30904
[Indexed for MEDLINE]
Free PMC Article

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