Stimulation of α2-adrenergic receptor inhibits cholangiocarcinoma growth through modulation of Raf-1 and B-Raf activities
2002; Lippincott Williams & Wilkins; Volume: 35; Issue: 6 Linguagem: Inglês
10.1053/jhep.2002.33330
ISSN1527-3350
AutoresNoriatsu Kanno, Gene LeSage, Jo Lynne Phinizy, Shannon Glaser, Heather Francis, Gianfranco Alpini,
Tópico(s)Cancer, Stress, Anesthesia, and Immune Response
ResumoGrowth factor signaling, mediated by the mitogen-activated protein kinase (MAPK) cascade, induces cell mitosis. Adenosine 3',5'-monophosphate (cAMP) may inhibit or stimulate mitosis (depending on the cell type) through the activation of MAPK and Raf proteins. Among Raf proteins, Raf-1 and B-Raf differentially regulate mitosis. Our aims were to evaluate the role and mechanisms of action of the α 2 -adrenergic agonist UK14,304 in the regulation of growth of the human cholangiocarcinoma cell line Mz-ChA-1. Immunocytochemistry and immunoblotting for α 2A -, α 2B -, or α 2C -adrenergic receptor subtypes showed positive reaction in Mz-ChA-1 cells. We found that physiological concentrations of UK14,304 increased cAMP levels and inhibited proliferation and MAPK activity in Mz-ChA-1 cells. Mz-ChA-1 cells expressed Raf-1 and B-Raf. Epidermal growth factor (EGF) immediately and transiently stimulated Raf-1 activity, whereas B-Raf activity was increased with prolonged EGF stimulation. EGF-stimulated Raf-1 and B-Raf activities were both inhibited by UK14,304. UK14,304 did not affect Ras activity. In Mz-ChA-1 cells, α 2 -adrenoreceptor stimulation causes up-regulation of cAMP, which inhibits EGF-induced MAPK activity through an acute increase of Raf-1 and sustained activation of B-Raf. In conclusion, because α 2 -AR inhibition of growth occurred downstream of Ras, adrenergic stimulation or other stimulants of cAMP may overcome the Ras mutations and offer a new therapeutic approach for patients with cholangiocarcinoma.
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