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

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, r espectively, and by acting via CB1-like cannabinoid receptors, However, the intracellular signals that mediate these effects are not known, Here, se s how that, in MCF-7 cells: (i) forskolin and the mitogen-activated protein k inase (MAPK) kinase inhibitor PD098059 pre,ent, and the protein kinase A in hibitor RpcAMPs mimics, the inhibitory effects of ANA on cell proliferation and PRLr/trk expression and (ii) ANA inhibits forskolin-induced cAMP forma tion and stimulates Raf-l translocation and MAPK: activity, in a fashion se nsitive 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 cel ls, ANA inhibits adenylyl cyclase and activates MAPK, thereby exerting a do wn-regulation on PRLr and trk levels and a suppression of cell proliferatio n. (C) 1999 Federation of European Biochemical Societies.