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

Significance Statement

MNF is abivalent ligand for the treatment of neoplastic diseases

Initial studies with (R,R’)-4’-methoxy-1-naphthylfenoterol (MNF) demonstrated that this drug is a highly selective and potent agonist at the {beta}2-adrenergic receptor, which effectively inhibits the proliferation of glioblastoma and astrocytoma brain tumors in vitro and in vivo (Toll et al., 2011; Bernier et al., 2013). Further studies with human hepatocellular carcinomas and pancreatic cancer cell lines indicated that MNF also inhibited the growth of these tumors but that the {beta}2-adrenergic receptor was not involved in this effect (Paul et al., 2012). The current paper (Paul et al., 2014) demonstrates that the observed anti-proliferative effects of MNF are also due to the inhibition of the GRP55 receptor, a cell surface membrane protein whose expression is increased in cancer.  Thus, MNF is a bivalent ligand that acts as an agonist at the {beta}2-adrenergic receptor and as an antagonist at the GPR55 receptor. A bivalent ligand is a single chemical entity composed of two covalently linked pharmacophores(Lane et al., 2013). Current studies utilizing tumor-derived cell lines have associated one or both of these functions with anti-tumor activities in a broad range of cancers and indicate that the pretreatment determination of receptor expression in the target tumor can be used to individualize and optimize the clinical use of MNF.

 

References:

Toll L, Jimenez L, Waleh N, Jozwiak K, Woo AY, Xiao RP, Bernier M, Wainer IW. (2011) Beta2-adrenergic receptor agonists inhibit the proliferation of 1321N1 astrocytoma cells.J PharmacolExpTher. 336:524-532.

Bernier M, Paul RK, Dossou KSS, Wnorowski A, Ramamoorthy A, Paris A, Moaddel R, Cloix JF, Wainer IW. (2013) Antitumor activity of (R,R’)-4-methoxy-1-naphthylfenoterol in a rat C6 gliomaxenograft model in the mouse. Pharma Res Per. 1:e00010.

Paul RK, Ramamoorthy A, Scheers J, Wersto RP, Toll L, Jimenez L, Bernier M, Wainer IW.

(2012) Cannabinoid receptor activation correlates with the proapoptotic action of the {Beta}2-adrenergic agonist (R,R’)-4-methoxy-1-naphthylfenoterol in HepG2 hepatocarcinoma cells.J PharmacolExpTher. 343:157-166.

Paul RK, Wnorowski A, Gonzalez-Mariscal I, Nayak SK, Pajak K, Moaddel R, Indig FE, Bernier M, Wainer IW. (2014) (R,R’)-4′-methoxy-1-naphthylfenoterol targets GPR55-mediated ligand internalization and impairs cancer cell motility. BiochemPharmacol. 87:547-561.

Lane JR, Sexton PM, Christopoulos A. (2013) Bridging the gap: bitopic ligands of G-protein-coupled receptors.Trends Pharmacol Sci. 34:59-66.

 

 

Figure Legend: The bitopic compound MNF elicitsvaried receptor-mediated anti-tumorigenic responses.

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

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Paul RK, Wnorowski A, Gonzalez-Mariscal I, Nayak SK, Pajak K, Moaddel R, Indig FE, Bernier M, Wainer IW.

Biochem Pharmacol. 2014 ;87(4):547-61.

Show Affiliations

 Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA. Electronic address: [email protected] and

Laboratory of Medicinal Chemistry and Neuroengineering, Department of Chemistry, Medical University of Lublin, 20-093 Lublin, Poland. Electronic address: [email protected] and

Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA. Electronic address: [email protected] and

SRI International (S.K.N.), Harrisonburg, VA 22802, USA. Electronic address: [email protected] and

Laboratory of Medicinal Chemistry and Neuroengineering, Department of Chemistry, Medical University of Lublin, 20-093 Lublin, Poland. Electronic address: [email protected] and

Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA. Electronic address: [email protected] and

Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA. Electronic address: [email protected] and

Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA. Electronic address: [email protected] and

Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA. Electronic address: [email protected]

 

 

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 cellpretreatment with GPR55 agonists, including the atypical cannabinoid O-1602 and l-{Alpha}-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.

Published by Elsevier Inc.

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