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

Cellular Signalling
Artur WnorowskiIrving W Wainer

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 in...Continue Reading

Citations

Jul 26, 2017·International Journal of Cancer. Journal International Du Cancer·Michel BernierIrving W Wainer
May 28, 2020·Journal of Receptor and Signal Transduction Research·Michael G Z GhaliM Gazi Yaşargil
Nov 20, 2020·Circulation Research·Ying SongRui-Ping Xiao
Feb 11, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Krzysztof Jóźwiak, Anita Płazińska

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