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, respectively, and by acting via CB(1)-like cannabinoid receptors. However, the intracellular signals that mediate these effects are not known. Here, we show that, in MCF-7 cells: (i) forskolin and the mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 prevent, 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-1 translocation and MAPK activity, in a fashion sensitive to the selective CB(1) antagonist SR141716A. ANA stimulation of MAPK was enhanced by inhibitors of ANA hydrolysis. Forskolin inhibited MAPK and ANA-induced Raf-1 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.
Melck
D
D
Istituto per la Chimica di Molecole di Interesse Biologico, Consiglio Nazionale delle Ricerche, Via Toiano 6, 80072, Arco Felice, Italy.
Rueda
D
D
Galve-Roperh
I
I
De Petrocellis
L
L
Guzmán
M
M
Di Marzo
V
V
D001095:Arachidonic Acids / Q000494:pharmacology*; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015536:Down-Regulation; D063388:Endocannabinoids; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011388:Prolactin / Q000037:antagonists & inhibitors; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011981:Receptors, Prolactin / Q000187:drug effects; D000077285:Rimonabant; D014407:Tumor Cells, Cultured
D001095:Arachidonic Acids; D063388:Endocannabinoids; D005419:Flavonoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D011981:Receptors, Prolactin; D005576:Colforsin; D011388:Prolactin; D020932:Nerve Growth Factor; D000242:Cyclic AMP; D019908:Proto-Oncogene Proteins c-raf; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000077285:Rimonabant; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C078814:anandamide