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Biochem Pharmacol. 2014 Feb 15;87(4):547-61. doi: 10.1016/j.bcp.2013.11.020. Epub 2013 Dec 16.

(R,R')-4'-methoxy-1-naphthylfenoterol targets GPR55-mediated ligand internalization and impairs cancer cell motility.

Author information

1
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA. Electronic address: paulrk@mail.nih.gov.
2
Laboratory of Medicinal Chemistry and Neuroengineering, Department of Chemistry, Medical University of Lublin, 20-093 Lublin, Poland. Electronic address: artur.wnorowski@gmail.com.
3
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA. Electronic address: isabel.gonzalezmariscal@nih.gov.
4
SRI International (S.K.N.), Harrisonburg, VA 22802, USA. Electronic address: surendra.nayak@sri.com.
5
Laboratory of Medicinal Chemistry and Neuroengineering, Department of Chemistry, Medical University of Lublin, 20-093 Lublin, Poland. Electronic address: karolina.pajak@umlub.pl.
6
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA. Electronic address: moaddelru@grc.nia.nih.gov.
7
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA. Electronic address: indigfr@grc.nia.nih.gov.
8
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA. Electronic address: bernierm@mail.nih.gov.
9
Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA. Electronic address: wainerir@grc.nia.nih.gov.

Abstract

(R,R')-4'-Methoxy-1-naphthylfenoterol (MNF) promotes growth inhibition and apoptosis of human HepG2 hepatocarcinoma cells via cannabinoid receptor (CBR) activation. The synthetic CB1R inverse agonist, AM251, has been shown to block the anti-mitogenic effect of MNF in these cells; however, AM251 is also an agonist of the recently deorphanized, lipid-sensing receptor, GPR55, whose upregulation contributes to carcinogenesis. Here, we investigated the role of MNF in GPR55 signaling in human HepG2 and PANC-1 cancer cell lines in culture by focusing first on internalization of the fluorescent ligand Tocrifluor 1117 (T1117). Initial results indicated that cell pretreatment with GPR55 agonists, including the atypical cannabinoid O-1602 and l-α-lysophosphatidylinositol, dose-dependently reduced the rate of cellular T1117 uptake, a process that was sensitive to MNF inhibition. GPR55 internalization and signaling mediated by O-1602 was blocked by MNF in GPR55-expressing HEK293 cells. Pretreatment of HepG2 and PANC-1 cells with MNF significantly abrogated the induction of ERK1/2 phosphorylation in response to AM251 and O-1602. Moreover, MNF exerted a coordinated negative regulation of AM251 and O-1602 inducible processes, including changes in cellular morphology and cell migration using scratch wound healing assay. This study shows for the first time that MNF impairs GPR55-mediated signaling and, therefore, may have therapeutic potential in the management of cancer.

KEYWORDS:

Cell motility; Cellular morphology; G-protein coupled receptor; GPR55; Ligand internalization

PMID:
24355564
PMCID:
PMC3935314
DOI:
10.1016/j.bcp.2013.11.020
[Indexed for MEDLINE]
Free PMC Article

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