Targeting CYP2J2 to Enhance the Anti-Glioma Efficacy of Cannabinoid Receptor 2 Stimulation by Inhibiting the Pro-Angiogenesis Function of M2 Microglia.

Xuejiao Lei,Yihao Tao,Xuezhu Chen,Yulian Quan,Junlong Li

doi:10.3389/fonc.2020.574277

Abstract

Enhancing the therapeutic efficacy of anti-tumor drugs is essential for cancer management. Although cannabinoid receptor 2 (CB2R) stimulation exerts anti-tumor action in glioma cells by regulating cellular proliferation, differentiation, or apoptosis, selective CB2R agonist alone does not achieve a satisfactory therapeutic outcome. Herein, we aimed to evaluate the possible strategy for enhancing the anti-glioma efficacy of JWH133, a selective CB2R agonist. In this study, immunofluorescence and qRT-PCR were used to investigate microglia polarization. Tumor growth was monitored via bioluminescent imaging using the IVIS Spectrum System. The angiogenesis of human brain microvascular endothelial cells (HBMECs) was detected by the tube formation assay. qRT-PCR was used to investigate cytochrome P450 2J2 (CYP2J2) and 11,12-epoxyeicosatrienoic acid (11,12-EET) expression. Our results showed that administration of JWH133 significantly promoted microglial M2 polarization both in vitro and in vivo. The medium supernatant of M2 microglia induced by JWH133 treatment facilitated angiogenesis of HBMECs. CYP2J2 expression and 11,12-EET release in the supernatant of JWH133-induced M2 microglia were significantly upregulated. Treatment with 11,12-EET prompted HBMEC angiogenesis and glioma growth. CYP2J2 knockdown restrained the release of 11,12-EET and significantly enhanced the anti-tumor effect of JWH133 on glioma. This study showed that targeting CYP2J2 might be a beneficial strategy to enhance the anti-glioma efficacy of JWH133 by inhibiting the pro-angiogenesis function of M2 microglia.

Highlights

Cannabinoids, the active components of Cannabis sativa and their derivatives, are known to exert their effects on a wide spectrum of diseases such as nervous system diseases, glaucoma, asthma, cardiovascular diseases, and tumors [1, 2]
The PCR assays were consistent with this finding that the mRNA expression level of CD206, IL4, and IL10 were significantly increased in M2 microglia (**P
We found that cytochrome P450 2J2 (CYP2J2) knockdown significantly reversed JWH133’s contribution to the increase of 11,12-EET, indicating that JWH133 promoted the expression of CYP2J2; CYP2J2 metabolized more arachidonic acid to 11,12EET in the microglia

Summary

Introduction

Cannabinoids, the active components of Cannabis sativa and their derivatives, are known to exert their effects on a wide spectrum of diseases such as nervous system diseases, glaucoma, asthma, cardiovascular diseases, and tumors [1, 2]. In the central nervous system (CNS), CB1R is mainly distributed in the presynaptic membranes of nerve terminals and regulates the release of neurotransmitters to mediate cannabinoid psychoactivity [5]. CB2R, mainly located in the glial cells, is not known to mediate psychoactivity but plays an important role in immune regulation and inhibition of cytokine release [6, 7], which has been well documented in treating neurological diseases such as neurodegeneration disorders [8], multiple sclerosis [9], stroke [10], and spinal cord injury [11] by modulating microglial activities. Little is known about the effect of CB2 stimulation on microglia/ macrophages in glioma

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