Canna~Fangled Abstracts

(R,R')-4'-Methoxy-1-naphthylfenoterol Targets GPR55-mediated Ligand Internalization and Impairs Cancer Cell Motility.

By December 21, 2013No Comments
Biochem Pharmacol. 2013 Dec 16. pii: S0006-2952(13)00754-5. doi: 10.1016/j.bcp.2013.11.020. [Epub ahead of print]

pm8(R,R’)-4′-Methoxy-1-naphthylfenoterol Targets GPR55-mediated Ligand Internalization and Impairs Cancer Cell Motility.

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 atypicalcannabinoid 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.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

(R)-(+)-[2,3-Dihydro-5-methyl-3-(4–morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin–6-yl]-1-naphthalenylmethanone, (R,R′)-4′-methoxy-1-naphthylfenoterol, (SR141716A,N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride), 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide, 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol, 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone, AM251, AM630, CBR, CP55,940, Cell motility, Cellular morphology, DIC, Differential Interference Contrast, EGF receptor, EGFR, G-protein coupled receptor, GPR55, L-α-lysophosphatidylinositol, LPI, Ligand internalization, MNF, O-1602, ROI, T1117, Tocrifluor 1117, WIN 55,212-2, [5-methyl-4-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-1,3-benzenediol, beta2 adrenoreceptor, cannabinoid receptor, region of interest, rimonabant, β2-AR

PMID:

 24355564
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