Epinephrine stimulates esophageal squamous-cell carcinoma cell proliferation via β-adrenoceptor-dependent transactivation of extracellular signal-regulated kinase/cyclooxygenase-2 pathway

Abstract

Esophageal cancer is the sixth leading causes of cancer-related death in the world. It is suggested that β-adrenoceptor is involved in the control of cell proliferation, but its role in the pathogenesis of esophageal cancer remains unknown. We therefore studied the role of β-adrenergic signaling in the regulation of growth of an esophageal squamous-cell carcinoma cell line HKESC-1. Results showed that both β1- and β2- adrenoceptors were expressed in HKESC-1 cells. Stimulation of β-adrenoceptors with epinephrine significantly increased HKESC-1 cell proliferation accompanied by elevation of intracellular cyclic AMP levels, which were abolished by β1- or β2-selective antagonists. Epinephrine also increased extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation as well as cyclooxygenase-2 (COX-2) and cytosolic phospholipase A2 expression, which were blocked by β1- or β2-selective antagonists. Moreover, epinephrine increased cyclin D1, cyclin E2, cyclin-dependent kinase (CDK)-4, CDK-6, and E2F-1 expression and retinoblastoma protein phosphorylation at Ser807/811, all of which were abrogated by β1-adrenoceptor antagonist. Furthermore, epinephrine increased the expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1 and -2 in a β2-adrenoceptor-, mitogen-activated protein kinase/ERK kinase (MEK)-, and COX-2-dependent manner. MEK or COX-2 inhibitor also significantly inhibited HKESC-1 cell proliferation induced by epinephrine. Collectively, we demonstrate that epinephrine stimulates esophageal squamous-cell carcinoma cell proliferation via β-adrenoceptor- dependent transactivation of ERK/COX-2 pathway. Stimulation of β1- and β2-adrenoceptors also elicits a differential response on the expression of cell cycle regulators. These novel findings may shed new light on the understanding of β-adrenergic signaling in the control of esophageal cancer cell growth. © 2008 Wiley-Liss, Inc.