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GPR55 receptor antagonist decreases glycolytic activity in PANC‐1 pancreatic cancer cell line and tumor xenografts
Author(s) -
Bernier Michel,
Catazaro Jonathan,
Singh Nagendra S.,
Wnorowski Artur,
BoguszewskaCzubara Anna,
Jozwiak Krzysztof,
Powers Robert,
Wainer Irving W.
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30904
Subject(s) - glycolysis , warburg effect , protein kinase b , carnitine , biology , glucose transporter , endocrinology , carbohydrate metabolism , pi3k/akt/mtor pathway , medicine , hexokinase , pyruvate kinase , chemistry , metabolism , signal transduction , biochemistry , insulin
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.