Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, UK.
Laboratory for Molecular Cell Biology, University College London, London, UK.
Br J Pharmacol. 2021 Mar;178(5):1149-1163. doi: 10.1111/bph.15351. Epub 2021 Jan 18.
Cannabidiol (CBD) has been shown to differentially regulate the mechanistic target of rapamycin complex 1 (mTORC1) in preclinical models of disease, where it reduces activity in models of epilepsies and cancer and increases it in models of multiple sclerosis (MS) and psychosis. Here, we investigate the effects of phytocannabinoids on mTORC1 and define a molecular mechanism.
A novel mechanism for phytocannabinoids was identified using the tractable model system, Dictyostelium discoideum. Using mouse embryonic fibroblasts, we further validate this new mechanism of action. We demonstrate clinical relevance using cells derived from healthy individuals and from people with MS (pwMS).
Both CBD and the more abundant cannabigerol (CBG) enhance mTORC1 activity in D. discoideum. We identify a mechanism for this effect involving inositol polyphosphate multikinase (IPMK), where elevated IPMK expression reverses the response to phytocannabinoids, decreasing mTORC1 activity upon treatment, providing new insight on phytocannabinoids' actions. We further validated this mechanism using mouse embryonic fibroblasts. Clinical relevance of this effect was shown in primary human peripheral blood mononuclear cells, where CBD and CBG treatment increased mTORC1 activity in cells derived from healthy individuals and decreased mTORC1 activity in cells derived from pwMS.
Our findings suggest that both CBD and the abundant CBG differentially regulate mTORC1 signalling through a mechanism dependent on the activity of the upstream IPMK signalling pathway, with potential relevance to the treatment of mTOR-related disorders, including MS.
大麻二酚（CBD）已被证明可在疾病的临床前模型中差异调节雷帕霉素靶蛋白复合物 1（mTORC1），在癫痫和癌症模型中降低其活性，而在多发性硬化症（MS）和精神病模型中增加其活性。在这里，我们研究了植物大麻素对 mTORC1 的影响，并定义了一种分子机制。
使用可处理的盘基网柄菌（Dictyostelium discoideum）模型系统，确定了植物大麻素的新作用机制。使用小鼠胚胎成纤维细胞，我们进一步验证了这种新的作用机制。我们使用来自健康个体和多发性硬化症患者（pwMS）的细胞证明了临床相关性。
CBD 和更丰富的大麻萜酚（CBG）均增强了盘基网柄菌中的 mTORC1 活性。我们确定了这种作用的机制涉及肌醇多磷酸激酶（IPMK），其中升高的 IPMK 表达逆转了对植物大麻素的反应，在治疗时降低 mTORC1 活性，为植物大麻素的作用提供了新的见解。我们使用小鼠胚胎成纤维细胞进一步验证了这种机制。这种作用的临床相关性在原代人外周血单核细胞中得到了证明，其中 CBD 和 CBG 处理增加了来自健康个体的细胞中的 mTORC1 活性，并降低了来自 pwMS 的细胞中的 mTORC1 活性。
我们的发现表明，CBD 和丰富的 CBG 通过依赖上游 IPMK 信号通路活性的机制，差异调节 mTORC1 信号，这可能与治疗与 mTOR 相关的疾病有关，包括 MS。
