Cannabinoid receptor 1 promotes hepatocellular carcinoma initiation and progression through multiple mechanisms

Abstract

Hepatocellular carcinoma (HCC) has high mortality and no adequate treatment. Endocannabinoids interact with hepatic CB1 receptors (CB1R) to promote hepatocyte proliferation in liver regeneration via inducing cell-cycle proteins involved in mitotic progression, including Forkhead Box M1 (FOXM1). Because FOXM1 is highly expressed in HCC and contributes to its genesis and progression, we analyzed the involvement of the endocannabinoid/CB1R system in murine and human HCC. Postnatal diethylnitrosamine (DEN) treatment induced HCC within 8 months in wild-type mice, but fewer and smaller tumors in CB1R−/− mice or in wild-type mice treated with the peripheral CB1R antagonist JD5037, as monitored in vivo by serial magnetic resonance imaging. Genome-wide transcriptome analysis revealed CB1R-dependent, tumor-induced upregulation of the hepatic expression of CB1R, its endogenous ligand anandamide, and a number of tumor promoting genes, including the GRB2 interactome as well as FOXM1 and its downstream target the tryptophan-catalyzing enzyme indoleamine 2,3-dioxygenase (IDO2). Increased IDO2 activity and consequent induction of immunosuppressive Treg cells in tumor tissue promote immune tolerance. Conclusion The endocannabinoid/CB1R system is upregulated in chemically induced HCC resulting in the induction of various tumor promoting genes, including IDO2, and attenuation of these changes by blockade or genetic ablation of CB1R suppresses the growth of HCC and highlights the therapeutic potential of peripheral CB1R blockade.

The use of cannabinoids as anticancer agents

“…A similar situation has been proposed for cannabinoid receptors and endocannabinoid degrading enzymes. Thus, CB1 receptor was found to be upregulated in Hodgkin lymphoma cells (Benz et al, 2013) and in chemically induced cellular hepatocarcinoma (Mukhopadhyay et al, 2015). CB1 receptors levels are also increased and correlate with disease severity in human epithelial ovarian tumors (Messalli et al, 2014) and have been proposed to be a factor of bad prognosis following surgery in stage IV colorectal cancer (Jung et al, 2013) Regarding CB2 receptor, a correlation between its expression, histologic grade and prognosis has been demonstrated in breast cancer (Caffarel et al, 2006) and glioma (Sanchez et al, 2001).…”

“…Moreover, genetic ablation of CB1 receptor suppresses the growth of hepatocarcinoma cellular (Mukhopadhyay et al, 2015).…”

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

“…The demonstrated ability of MRI-1867 to attenuate diet-induced obesity and its metabolic consequences may also contribute to its efficacy in mitigating liver fibrosis when obesity is a contributing factor. Furthermore, CB 1 R blockade has therapeutic potential not only in conditions that predispose to fibrosis, but also in hepatocellular carcinoma (40), which has been epidemiologically linked to progressive liver fibrosis (41, 42). …”

Cannabinoid pharmacology in cancer research: A new hope for cancer patients?

“…The over expression of cannabinoid receptors and elevated endocannabinoid levels have also been reported in a variety of different cancer types such as prostate, skin, hepatocellular carcinoma, colon, endometrial sarcoma, glioblastoma multiforme (GBM), meningioma and pituitary adenoma (see table 1) Xu et al, 2006;Pisanti et al, 2013). CB 1 receptors are also up-regulated in Hodgkin lymphoma cells and also in chemically induced hepatocarcinoma (Benz et al, 2013;Mukhopadhyay et al, 2015). Also the expression of CB 1 and CB 2 receptors was found to increase in mantel cell lymphoma and fatty acid amide hydrolase (FAAH) expression was reduced when compared to non-malignant B-cells (Islam et al, 2003;Ek et al, 2002;Wasik et al, 2014).…”