GPR55 Receptor Activation by the N-Acyl Dopamine Family Lipids Induces Apoptosis in Cancer Cells via the Nitric Oxide Synthase (nNOS) Over-Stimulation.

Mikhail G Akimov,Alina M Gamisonia,Andrey S Kuznetsov,Galina N Zinchenko,Polina V Dudina,Anastasia A Gaydaryova,Natalia M Gretskaya,Vladimir V Bezuglov

doi:10.3390/ijms22020622

Mikhail G Akimov, Alina M Gamisonia + Show 6 more

Open Access

https://doi.org/10.3390/ijms22020622

Copy DOI

Abstract

GPR55 is a GPCR of the non-CB1/CB2 cannabinoid receptor family, which is activated by lysophosphatidylinositol (LPI) and stimulates the proliferation of cancer cells. Anandamide, a bioactive lipid endocannabinoid, acts as a biased agonist of GPR55 and induces cancer cell death, but is unstable and psychoactive. We hypothesized that other endocannabinoids and structurally similar compounds, which are more hydrolytically stable, could also induce cancer cell death via GPR55 activation. We chemically synthesized and tested a set of fatty acid amides and esters for cell death induction via GPR55 activation. The most active compounds appeared to be N-acyl dopamines, especially N-docosahexaenoyl dopamine (DHA-DA). Using a panel of cancer cell lines and a set of receptor and intracellular signal transduction machinery inhibitors together with cell viability, Ca2+, NO, ROS (reactive oxygen species) and gene expression measurement, we showed for the first time that for these compounds, the mechanism of cell death induction differed from that published for anandamide and included neuronal nitric oxide synthase (nNOS) overstimulation with concomitant oxidative stress induction. The combination of DHA-DA with LPI, which normally stimulates cancer proliferation and is increased in cancer setting, had an increased cytotoxicity for the cancer cells indicating a therapeutic potential.

Highlights

GPR55 is a G-protein coupled receptor (GPCR) of the non-CB1/CB2 cannabinoid receptor family [1]
The LPI signal is transduced via Ras homolog family member A (RhoA) or Ca2+ to extracellular signal-regulated kinase (ERK) and nuclear factor of activated T-cells (NFAT), leading to an increase of cell proliferation [1]
We showed for the first time that the mechanism of cell death induction by these compounds differed from that of anandamide and included neuronal nitric oxide synthase overstimulation with concomitant oxidative stress induction

Summary

Introduction

GPR55 is a G-protein coupled receptor (GPCR) of the non-CB1/CB2 cannabinoid receptor family [1]. The natural ligand of GPR55 is thought to be lysophasphatidylinositol (LPI); it usually activates the receptor in the concentration range of 0.5–4 μM. Other bioactive lipids of the endocannabinoid family like 2-arachidonoylglycerol and anandamide (AA-EA) are able to activate GPR55 or serve as its inverse agonists [3]. GPR55 is widely expressed in various cancers and is usually associated with the late stages and bad prognosis of the disease [2]. The molecular mechanism of this association is the induction of cell proliferation after receptor activation by its natural agonist LPI, which is abundantly synthesized and released by cancer cells [4]. The LPI signal is transduced via Ras homolog family member A (RhoA) or Ca2+ to extracellular signal-regulated kinase (ERK) and nuclear factor of activated T-cells (NFAT), leading to an increase of cell proliferation [1]

Methods

Discussion

Conclusion