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Cell Signal. 2017 Aug;36:176-188. doi: 10.1016/j.cellsig.2017.05.006. Epub 2017 May 8.

Concurrent activation of β2-adrenergic receptor and blockage of GPR55 disrupts pro-oncogenic signaling in glioma cells.

Author information

1
Laboratory of Clinical Investigation, Baltimore, MD 21224, USA; Department of Biopharmacy, Medical University of Lublin, 23-093 Lublin, Poland. Electronic address: artur.wnorowski@umlub.pl.
2
Department of Biopharmacy, Medical University of Lublin, 23-093 Lublin, Poland. Electronic address: justyna.such@wp.pl.
3
Laboratory of Clinical Investigation, Baltimore, MD 21224, USA.
4
Flow Cytometry Unit, Baltimore, MD 21224, USA. Electronic address: werstor@grc.nia.nih.gov.
5
Laboratory of Cardiovascular Science, Baltimore, MD 21224, USA. Electronic address: indigfr@grc.nia.nih.gov.
6
Department of Biopharmacy, Medical University of Lublin, 23-093 Lublin, Poland. Electronic address: krzysztof.jozwiak@umlub.pl.
7
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: bernierm@mail.nih.gov.
8
Laboratory of Clinical Investigation, Baltimore, MD 21224, USA; Mitchell Woods Pharmaceuticals, LLC, Shelton, CT 06484, USA. Electronic address: iwwainer@mitchellwoods.com.

Abstract

Activation of β2-adrenergic receptor (β2AR) and deorphanized GPR55 has been shown to modulate cancer growth in diverse tumor types in vitro and in xenograft models in vivo. (R,R')-4'-methoxy-1-naphthylfenoterol [(R,R')-MNF] is a bivalent compound that agonizes β2AR but inhibits GPR55-mediated pro-oncogenic responses. Here, we investigated the molecular mechanisms underlying the anti-tumorigenic effects of concurrent β2AR activation and GPR55 blockade in C6 glioma cells using (R,R')-MNF as a marker ligand. Our data show that (R,R')-MNF elicited G1-phase cell cycle arrest and apoptosis, reduced serum-inducible cell motility, promoted the phosphorylation of PKA target proteins, and inhibited constitutive activation of ERK and AKT in the low nanomolar range, whereas high nanomolar levels of (R,R')-MNF were required to block GPR55-mediated cell motility. siRNA knockdown and pharmacological inhibition of β2AR activity were accompanied by significant upregulation of AKT and ERK phosphorylation, and selective alteration in (R,R')-MNF responsiveness. The effects of agonist stimulation of GPR55 on various readouts, including cell motility assays, were suppressed by (R,R')-MNF. Lastly, a significant increase in phosphorylation-mediated inactivation of β-catenin occurred with (R,R')-MNF, and we provided new evidence of (R,R')-MNF-mediated inhibition of oncogenic β-catenin signaling in a C6 xenograft tumor model. Thus, simultaneous activation of β2AR and blockade of GPR55 may represent a novel therapeutic approach to combat the progression of glioblastoma cancer.

KEYWORDS:

Bivalent ligand; Brain cancer; Cannabinoid receptor; Fenoterol derivative; Invasiveness

PMID:
28495590
PMCID:
PMC5512002
DOI:
10.1016/j.cellsig.2017.05.006
[Indexed for MEDLINE]
Free PMC Article

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