MDA19, a novel CB2 agonist, inhibits hepatocellular carcinoma partly through inactivation of AKT signaling pathway

Mei Rao,Jianqing Jiang,Dongfeng Chen,Peng Zhan

doi:10.1186/s13062-019-0241-1

Abstract

BackgroundCB2 (cannabinoid receptor 2) agonists have been shown to exert anti-tumor activities in different tumor types. However, there is no study exploring the role of MDA19 (a novel CB2 agonist) in tumors. In this study we aimed to investigate the effects of MDA19 treatment on HCC cell lines, Hep3B and HepG2 and determine the relevant mechanisms.ResultsCell proliferation analysis, including CCK8 and colony formation assays, indicated that MDA19 treatment inhibited HCC cell proliferation in a dose- and time-dependent manner. Flow cytometry suggested that MDA19 induced cell apoptosis and activation of mitochondrial apoptosis pathway. Transwell assay indicated that HCC cell migration and invasion were significantly inhibited by MDA19 treatment. Mechanism investigation suggested that MDA19 induced inactivation of AKT signaling pathway in HCC cells. In addition, we investigated the function of CB2receptor in HCC and its role in the anti-tumor activity of MDA19. By searching on Kaplan-Meier plotter (http://kmplot.com/analysis/), we found that HCC patients with high CB2 expression had a better survival and CB2 expression was significantly associated with gender, clinical stages and race of HCC patients (P < 0.05). CB2 inhibited the progression of HCC cells and its knockdown could rescue the growth inhibition induced by MDA19 in HCC. Moreover, the inhibitory effect of MDA19 on AKT signaling pathway was also reversed by CB2 knockdown.ConclusionOur data suggest that MDA-19 exerts an anti-tumor activity at least partly through inactivation of AKT signaling pathway in HCC. CB2 functions as a tumor suppressor gene in HCC, and MDA19-induced growth inhibition of HCC cells depends on its binding to CB2 to activate it. MDA-19 treatment may be a promising strategy for HCC therapy.ReviewerThis article was reviewed by Tito Cali, Mohamed Naguib and Bo Chen.

Highlights

cannabinoid receptor 2 (CB2) agonists have been shown to exert anti-tumor activities in different tumor types
The results suggested that MDA19 inhibited Hepatocellular carcinoma (HCC) cell proliferation in a dose- and timedependent manner
We investigated the relationship between CB2 expression and the survival rate of HCC patients on Kaplan-Meier plotter, suggesting that the Conclusions In conclusion, these data suggest that MDA-19 exerts an anti-tumor activity at least partly through inhibiting AKT signaling pathway in HCC

Summary

Introduction

CB2 (cannabinoid receptor 2) agonists have been shown to exert anti-tumor activities in different tumor types. There is no study exploring the role of MDA19 (a novel CB2 agonist) in tumors. In recent years it has been found that Cannabinoids exert anti-tumor activities by inducing tumor cell death, cell cycle arrest or inhibiting tumor angiogenesis [7, 8]. N′-[(3Z)-1-(1-hexyl)-2-oxo-1, 2-dihydro-3H-indol-3-ylidene] benzohydrazide (MDA19), as a selective agonist for CB1 and CB2, has been demonstrated to play an important role in relieving neuropathic pain without a potential adverse effect on the central nervous system [10]. Some agonists of CB2 or CB1 have been shown to exert anti-tumor activity in some tumor models [12,13,14]. There is currently no study on the role of MDA19 in tumors

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