Involvement of the cAMP/protein kinase A pathway and of mitogen-activated protein kinase in the anti-proliferative effects of anandamide in human breast cancer cells
Involvement of the cAMP/protein kinase A pathway and of mitogen-activated protein kinase in the anti-proliferative effects of anandamide in human breast cancer cells
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DOI：
10.1016/s0014-5793(99)01639-7
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发表时间：
1999-12-17
期刊：
影响因子：
3.5
通讯作者：
Di Marzo, V
中科院分区：
文献类型：
--
作者：
Melck, D;Rueda, D;Di Marzo, V
花生四烯酸（ANA）通过分别降低100 kDa催乳素受体（PRLr）和高亲和力trk NGF受体的水平，以及通过CB 1样大麻素受体起作用，抑制催乳素和神经生长因子（NGF）诱导的人乳腺癌细胞增殖。然而，介导这些作用的细胞内信号尚不清楚。（i）毛喉素和促分裂原活化蛋白激酶（MAPK）激酶抑制剂PD 098059前体和蛋白激酶A抑制剂RpcAMPs模拟ANA对细胞增殖和PRLr/trk表达的抑制作用，以及（ii）ANA抑制毛喉素诱导的cAMP形成并刺激Raf-l易位和MAPK：活性，以对选择性CB 1拮抗剂SR 141716 A敏感的方式。ANA水解抑制剂可增强ANA对MAPK的刺激作用。这些结果表明，在MCF-7细胞中，ANA抑制腺苷酸环化酶并激活MAPK，从而下调PRLr和trk水平，抑制细胞增殖。(C)1999年欧洲生物化学学会联合会。
Anandamide (ANA) inhibits prolactin- and nerve growth factor (NGF)-induced proliferation of human breast cancer cells by decreasing the levels of the 100 kDa prolactin receptor (PRLr) and the high affinity trk NGF receptor, respectively, and by acting via CB1-like cannabinoid receptors, However, the intracellular signals that mediate these effects are not known, Here, se show that, in MCF-7 cells: (i) forskolin and the mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 pre,ent, and the protein kinase A inhibitor RpcAMPs mimics, the inhibitory effects of ANA on cell proliferation and PRLr/trk expression and (ii) ANA inhibits forskolin-induced cAMP formation and stimulates Raf-l translocation and MAPK: activity, in a fashion sensitive to the selective CB1 antagonist SR141716A. ANA stimulation of MAPK mas enhanced by inhibitors of ANA hydrolysis. Forskolin inhibited MAPK and ANA-induced Raf-l translocation, These findings indicate that, in MCF-7 cells, ANA inhibits adenylyl cyclase and activates MAPK, thereby exerting a down-regulation on PRLr and trk levels and a suppression of cell proliferation. (C) 1999 Federation of European Biochemical Societies.