Abstract 5516: (R,R’)-4’-methoxy-1-naphthylfenoterol Inhibits GPR55 signaling and the modulation of motility in human cancer cells.

Abstract

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 GPR55 in MNF signaling in human HepG2 and PANC-1 cancer cell lines in culture, with a focus on internalization of the fluorescent ligand Tocrifluor 1117 (T1117), reorganization of actin cytoskeleton, and cell motility as measured by scratch assay. Control experiments indicated that GPR55 knockdown by RNA interference markedly reduced cellular uptake of T1117, a process that was sensitive to MNF inhibition. GPR55 internalization mediated by the atypical cannabinoid 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 ERK phosphorylation in response to AM251, O-1602 and fetal bovine serum, known to contain bioactive lipids. Moreover, MNF exerted a coordinated regulation of AM251 and O-1602 inducible processes, including cell motility. This study shows for the first time that MNF impairs GPR55-mediated signaling and, therefore, may have therapeutic potential for the management of cancer. This work was supported entirely by the Intramural Research Program of the NIA, NIH. Citation Format: Rajib K. Paul, Artur Wnorowski, Isabel Gonzalez-Mariscal, Ruin Moaddel, Fred E. Indig, Irving W. Wainer, Michel Bernier. (R,R’)-4’-methoxy-1-naphthylfenoterol Inhibits GPR55 signaling and the modulation of motility in human cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5516. doi:10.1158/1538-7445.AM2013-5516