Bladder cancer cell growth and motility implicate cannabinoid 2 receptor-mediated modifications of sphingolipids metabolism.
Bladder cancer cell growth and motility implicate cannabinoid 2 receptor-mediated modifications of sphingolipids metabolism.
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DOI：
10.1038/srep42157
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发表时间：
2017-02-13
影响因子：
4.6
通讯作者：
Benigni F
中科院分区：
文献类型：
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作者：
Bettiga A;Aureli M;Colciago G;Murdica V;Moschini M;Lucianò R;Canals D;Hannun Y;Hedlund P;Lavorgna G;Colombo R;Bassi R;Samarani M;Montorsi F;Salonia A;Benigni F
大麻素受体（CB）对癌症增殖和迁移的抑制作用也可能在控制膀胱癌（BC）中发挥关键作用。采用免疫组化方法检测CB在正常人和BC标本中的表达。用CB激动剂攻击人BC细胞RT 4和RT 112，并评估增殖、凋亡和运动性。代谢标记后，细胞鞘脂（SL）的构成和代谢进行了评估。在BC标本中检测到CB 1 -2，但只有CB 2在肿瘤中表达更多。两种细胞系表达相似的CB 2。暴露于CB 2激动剂抑制BC生长，下调Akt，诱导半胱天冬酶3激活和修改SL代谢。细胞系中的基线SL分析显示与独特的迁移行为和细胞骨架重排相关的差异。CB 2激活通过减少（p < 0.01）Gb 3神经节苷脂（−50 ± 3%）和1-磷酸鞘氨醇（S1 P，−40 ± 4%）改变了更具攻击性的RT 112细胞的SL组成，最终导致细胞运动性降低（−46 ± 5%）并抑制p-SRC。CB 2选择性拮抗剂，基因沉默和SL生物合成的抑制剂部分阻止CB 2激动剂诱导的细胞活力和运动性的影响。CB 2激活导致神经酰胺介导的BC细胞凋亡，而不依赖于SL组成型组合物，其反而由CB 2激动剂调节以降低细胞运动性。
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.