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

Biochemical Pharmacology
Rajib K PaulIrving W Wainer

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...Continue Reading

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Citations

Jun 27, 2014·Experimental Neurology·E Martínez-PinillaR Franco
Jan 21, 2016·Journal of Medicinal Chemistry·Paula MoralesNadine Jagerovic
Jul 18, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Nagendra S SinghIrving W Wainer
Jun 20, 2019·Frontiers in Pharmacology·Paula Morales, Nadine Jagerovic
May 15, 2015·Anti-cancer Drugs·Sara CarpiPaola Nieri
Feb 16, 2017·Journal of Molecular Endocrinology·Eva TuduríRubén Nogueiras

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