Abstract
G protein-coupled receptor 55 (GPR55) possesses pro-oncogenic activity and its function can be competitively inhibited with (R,R')-4'-methoxy-1-naphthylfenoterol (MNF) through poorly defined signaling pathways. Here, the anti-tumorigenic effect of MNF was investigated in the human pancreatic cancer cell line, PANC-1, by focusing on the expression of known cancer biomarkers and the expression and function of multidrug resistance (MDR) exporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Incubation of PANC1 cells with MNF (1μM) for 24h significantly decreased EGF receptor, pyruvate kinase M2 (PKM2), and β-catenin protein levels and was accompanied by significant reduction in nuclear accumulation of HIF-1α and the phospho-active forms of PKM2 and β-catenin. Inhibition of GPR55 with either MNF or the GPR55 antagonist CID 16020046 lowered the amount of MDR proteins in total cellular extracts while diminishing the nuclear expression of Pgp and BCRP. There was significant nuclear accumulation of doxorubicin in PANC-1 cells treated with MNF and the pre-incubation with MNF increased the cytotoxicity of doxorubicin and gemcitabine in these cells. Potentiation of doxorubicin cytotoxicity by MNF was also observed in MDA-MB-231 breast cancer cells and U87MG glioblastoma cells, which express high levels of GPR55. The data suggest that inhibition of GPR55 activity produces antitumor effects via attenuation of the MEK/ERK and PI3K-AKT pathways leading to a reduction in the expression and function of MDR proteins.
Keywords:
Cancer biomarkers; GPR55; Hypoxia-inducible factor 1α (HIF-1α); Multidrug resistance (MDR); Pyruvate kinase M2 (PKM2); β-Catenin.
Published by Elsevier Ltd.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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Antibiotics, Antineoplastic / metabolism
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Antibiotics, Antineoplastic / pharmacology*
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Antimetabolites, Antineoplastic / metabolism
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Antimetabolites, Antineoplastic / pharmacology
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Biomarkers, Tumor / metabolism
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Carrier Proteins / metabolism
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Cell Proliferation / drug effects
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / metabolism
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Deoxycytidine / pharmacology
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Dose-Response Relationship, Drug
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Doxorubicin / metabolism
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Doxorubicin / pharmacology*
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Drug Resistance, Neoplasm / drug effects*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fenoterol / analogs & derivatives*
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Fenoterol / pharmacology
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Gemcitabine
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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MCF-7 Cells
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Membrane Proteins / metabolism
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Phosphatidylinositol 3-Kinase / metabolism
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Cannabinoid
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Receptors, G-Protein-Coupled / antagonists & inhibitors*
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Signal Transduction / drug effects
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Thyroid Hormone-Binding Proteins
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Thyroid Hormones / metabolism
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beta Catenin / metabolism
Substances
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4'-methoxy-1-naphthylfenoterol
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ATP Binding Cassette Transporter, Subfamily B
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Antibiotics, Antineoplastic
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Antimetabolites, Antineoplastic
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Biomarkers, Tumor
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CTNNB1 protein, human
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Carrier Proteins
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GPR55 protein, human
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Membrane Proteins
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Receptors, Cannabinoid
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Receptors, G-Protein-Coupled
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Thyroid Hormones
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beta Catenin
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Deoxycytidine
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Fenoterol
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Doxorubicin
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Phosphatidylinositol 3-Kinase
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase Kinases
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Gemcitabine