TY - JOUR T1 - Epidermal Growth Factor-Induced Esophageal Cancer Cell Proliferation Requires Transactivation of β-Adrenoceptors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 69 LP - 75 DO - 10.1124/jpet.107.134528 VL - 326 IS - 1 AU - Xuan Liu AU - William K. K. Wu AU - Le Yu AU - Zhi J. Li AU - Joseph J. Y. Sung AU - Shu T. Zhang AU - Chi H. Cho Y1 - 2008/07/01 UR - http://jpet.aspetjournals.org/content/326/1/69.abstract N2 - Unchecked mitogenic signals due to the overexpression of epidermal growth factor (EGF) and its receptor (EGFR) is implicated in the promotion and progression of cancer. In addition, β-adrenoceptor is involved in the control of cancer cell proliferation. This study sought to elucidate whether a functional connection exists between these two disparate receptor systems. EGF was used to stimulate HKESC-1 cells, an esophageal squamous cancer cell line, in which β-adrenoceptor activity was monitored by measuring intracellular cAMP levels in the absence or presence of β-adrenoceptor antagonists. Results showed that EGF significantly increased cAMP levels and cell proliferation, both of which were attenuated by atenolol [(+)-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]benzeneacetamide] or ICI 118,551 [(±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol], which are antagonists for the β-adrenoceptor. Further mechanistic investigation revealed that the cellular release of epinephrine and the expression of its synthesizing enzyme tyrosine hydroxylase were induced by EGF. The expression of β1-adrenoceptor and the downstream signal transducer protein kinase A were also up-regulated. In this connection, AG1478 [4-(3-chloroanilino)-6,7-dimethoxyquinazoline], an EGFR tyrosine kinase inhibitor, abrogated all these EGF-elicited alteration. Collectively, this study demonstrates that β-adrenergic signaling could be up-regulated at multiple levels upon EGFR activation to mediate the mitogenic signals in esophageal cancer cells. This novel finding not only unveils the sinister liaison between EGFR and β-adrenoceptors but also sheds new light on the purported therapeutic use of β-adrenoceptor antagonists in the treatment of esophageal cancer. The American Society for Pharmacology and Experimental Therapeutics ER -