Abstract
The inhibitory effects demonstrated by activation of cannabinoid receptors (CB) on cancer proliferation and migration may also play critical roles in controlling bladder cancer (BC). CB expression on human normal and BC specimens was tested by immunohistochemistry. Human BC cells RT4 and RT112 were challenged with CB agonists and assessed for proliferation, apoptosis, and motility. Cellular sphingolipids (SL) constitution and metabolism were evaluated after metabolic labelling. CB1-2 were detected in BC specimens, but only CB2 was more expressed in the tumour. Both cell lines expressed similar CB2. Exposure to CB2 agonists inhibited BC growth, down-modulated Akt, induced caspase 3-activation and modified SL metabolism. Baseline SL analysis in cell lines showed differences linked to unique migratory behaviours and cytoskeletal re-arrangements. CB2 activation changed the SL composition of more aggressive RT112 cells by reducing (p < 0.01) Gb3 ganglioside (−50 ± 3%) and sphingosine 1-phosphate (S1P, −40 ± 4%), which ended up to reduction in cell motility (−46 ± 5%) with inhibition of p-SRC. CB2-selective antagonists, gene silencing and an inhibitor of SL biosynthesis partially prevented CB2 agonist-induced effects on cell viability and motility. CB2 activation led to ceramide-mediated BC cell apoptosis independently of SL constitutive composition, which instead was modulated by CB2 agonists to reduce cell motility.
Highlights
The inhibitory effects demonstrated by activation of cannabinoid receptors (CB) on cancer proliferation and migration may play critical roles in controlling bladder cancer (BC)
The expression of CB2 mRNA, analysed in silico by interrogating the Cancer Genome Atlas dataset available on cBioPortal for Cancer Genomics[14,15] in Bladder cancer (BC) patients, was found significantly higher in advanced tumours (Fig. 1F)
Exhaustive genomic and bioinformatics analysis of CB2 in BC is reported in supplemental results
Summary
The inhibitory effects demonstrated by activation of cannabinoid receptors (CB) on cancer proliferation and migration may play critical roles in controlling bladder cancer (BC). Human BC cells RT4 and RT112 were challenged with CB agonists and assessed for proliferation, apoptosis, and motility. CB2 activation led to ceramide-mediated BC cell apoptosis independently of SL constitutive composition, which instead was modulated by CB2 agonists to reduce cell motility. A variety of putative novel biomarkers or targets have been recently described for urothelial carcinoma[1] In this context, the endocannabinoid system (ECS) expressed by the genitourinary organs has recently gained particular attention[2]. The endocannabinoid system (ECS) expressed by the genitourinary organs has recently gained particular attention[2] Both clinical and experimental evidence suggested a possible role of the ECS in modulating cancer proliferation, progression, and metastasis[3] in several types of neoplastic diseases, including prostate and breast cancer[4,5]. The known antiproliferative activity of ECS modulators (i.e. cannabinoids) in various cancer models is reported to modify SL metabolism, which typically results in accumulation of ceramide (Cer) via de novo synthesis[11,12] and deregulation of the Cer/ S1P rheostat[13]
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