AbstractEsophageal 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. J. Cell. Biochem. 105: 53–60, 2008. © 2008 Wiley‐Liss, Inc.