Abstract
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.
Footnotes
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This study was supported by The Hong Kong Research Grants Council (CUHK 7499/05M).
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L.X. and W.K.K.W. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.134528.
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ABBREVIATIONS: EGFR, epidermal growth factor receptor; EGF, epidermal growth factor; PKA, protein kinase A; AG1478, 4-(3-chloroanilino)-6,7-dimethoxyquinazoline; atenolol, (+)-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]benzeneacetamide; ICI 118,551, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; PCR, polymerase chain reaction; Ate, atenolol; ICI, ICI 118,551; TH, tyrosine hydroxylase.
- Received November 20, 2007.
- Accepted March 26, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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