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

Background: CB₂ (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.

Results: Cell 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.

Conclusion: Our 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.

Reviewer: This article was reviewed by Tito Cali, Mohamed Naguib and Bo Chen.