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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Epidermal Growth Factor-Induced Esophageal Cancer Cell Proliferation Requires Transactivation of β-Adrenoceptors

Beijing Digestive Diseases Center and Beijing Friendship Hospital, Capital Medical University, Beijing, China (X.L., S.T.Z.); and Departments of Pharmacology (W.K.K.W., L.Y., Z.J.L., C.H.C.) and Medicine and Therapeutics (W.K.K.W., J.J.Y.S.) and Institute of Digestive Diseases (W.K.K.W., J.J.Y.S., C.H.C.), Chinese University of Hong Kong, Hong Kong, China

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.

Address correspondence to: Dr. Chi Hin Cho, Department of Pharmacology, 4/F Basic Medical Sciences Building, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. E-mail: chcho{at}cuhk.edu.hk