title: Epinephrine stimulates esophageal squamous-cell carcinoma cell proliferation via beta-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 beta-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 beta-adrenergic signaling in the regulation of growth of an esophageal squamous-cell carcinoma cell line HKESC-1. Results showed that both beta(1)- and beta(2)-adrenoceptors were expressed in HKESC-1 cells. Stimulation of beta-adrenoceptors with epinephrine significantly increased HKESC-1 cell proliferation accompanied by elevation of intracellular cyclic AMP levels, which were abolished by beta(1)- or beta(2)-selective antagonists. Epinephrine also increased extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation as well as cyclooxygenase-2 (COX-2) and cytosolic phospholipase A(2) expression, which were blocked by beta(1)- or beta(2)-selective antagonists. Moreover, epinephrine increased cyclin D(1), cyclin E(2), cyclin-dependent kinase (CDK)-4, CDK-6, and E(2)F-1 expression and retinoblastoma protein phosphorylation at Ser807/811, all of which were abrogated by beta(1)-adrenoceptor antagonist. Furthermore, epinephrine increased the expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1 and -2 in a beta(2)-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 beta-adrenoceptor-dependent transactivation of ERK/COX-2 pathway. Stimulation of beta(1)- and beta(2)-adrenoceptors also elicits a differential response on the expression of cell cycle regulators. These novel findings may shed new light on the understanding of beta-adrenergic signaling in the control of esophageal cancer cell growth.
authors.affiliation: Beijing Digestive Diseases Center and Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: William K K
authors.initials: WK
authors.lastname: Wu
authors.forename: Le
authors.initials: L
authors.lastname: Yu
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.forename: Gopesh
authors.initials: G
authors.lastname: Srivastava
authors.forename: Shu T
authors.initials: ST
authors.lastname: Zhang
authors.forename: Chi H
authors.initials: CH
authors.lastname: Cho
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D054513:Group IV Phospholipases A2 / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D016160:Retinoblastoma Protein; D042461:Vascular Endothelial Growth Factor A; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D054513:Group IV Phospholipases A2; D004837:Epinephrine