Involvement of p38 mitogen-activated protein kinase activation in bromocriptine-induced apoptosis in rat pituitary GH3 cells.
Bromocriptine, a dopamine D(2) receptor agonist, is a therapeutic agent for patients with prolactinoma and hyperprolactinemia. In this study we demonstrated that bromocriptine induced activation of p38 mitogen-activated protein (MAP) kinase, with concomitant induction of apoptosis in rat pituitary adenoma cell line GH3 cells. Treatment of GH3 cells for 48 h with bromocriptine increased the p38 MAP kinase activity up to 3- to 5-fold and simultaneously increased the number of apoptotic cells. Inclusion in the medium of SB212090 or SB203580, specific p38 MAP kinase inhibitors, completely abolished the bromocriptine-induced activation of p38 MAP kinase and significantly reduced the number of apoptotic cells. The bromocriptine-induced p38 MAP kinase activation was not prevented by S(-)-eticropride hydrochloride, a specific D(2) receptor antagonist. Treatment with either epidermal growth factor (EGF) or thyrotropin-releasing hormone (TRH), which stimulates p44/42 MAP kinase, rescued cells from the bromocriptine-induced apoptosis, with concomitant inhibition of the bromocriptine-induced p38 MAP kinase activation. These results suggest that bromocriptine induces apoptosis in association with p38 MAP kinase activation, and that the p44/42 MAP kinase signaling through EGF and TRH receptors has an opposing effect on p38 MAP kinase activation as well as on apoptosis induced with bromocriptine in GH3 cells.
Kanasaki
H
H
Department of Pharmacology, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan.
Fukunaga
K
K
Takahashi
K
K
Miyazaki
K
K
Miyamoto
E
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001971:Bromocriptine / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000201:enzymology* / Q000473:pathology; D015175:Prolactinoma / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000502:physiology; D015398:Signal Transduction; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D065127:Dopamine D2 Receptor Antagonists; D018025:Receptors, Thyrotropin-Releasing Hormone; D001971:Bromocriptine; D013973:Thyrotropin-Releasing Hormone; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases