Amlodipine,a Ca2+ channel blocker,suppresses phosphorylation of epidermal growth factor receptor in human epidermoid carcinoma A431 cells |
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Authors: | Junko Yoshida Takaharu Ishibashi Mei Yang Matomo Nishio |
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Affiliation: | 1. Department of Pharmacology, School of Medicine, Kanazawa Medical University, Daigaku 1-1, Uchinada, Ishikawa 920-0293, Japan;2. Department of Pharmacology, School of Nursing, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan |
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Abstract: | AimsAmlodipine, a dihydropyridine Ca2+ channel blocker, inhibits the proliferation of human epidermoid carcinoma A431 cells in vitro and in vivo. This study examined the underlying mechanism of this antiproliferative effect in relation to epidermal growth factor receptor (EGFR) signaling.Main methodsThe tyrosine phosphorylated active state of EGFR in A431 cells incubated with the test agents was evaluated by western blot with anti-phosphotyrosine antibody. EGFR phosphorylation levels in A431 xenograft tumors were assessed by immunostaining of matrigel plug sections and western blotting for phosphoEGFR in A431 xenograft tumor homogenates.Key findingsIn vitro treatment of exponentially growing A431 cells with amlodipine decreased the tyrosine phosphorylation states of EGFR. Amlodipine also suppressed the EGF-stimulated phosphorylation of EGFR and a membrane scaffolding protein, caveolin-1, in serum-starved A431 cells. Amlodipine attenuated the EGF-stimulated phosphorylation of EGFR coimmunoprecipitated with caveolin-1 without affecting the EGFR/caveolin-1 interaction. Crosslinking experiments showed that amlodipine also suppressed the EGF-stimulated phosphorylation of EGFR predimers. Addition of cholesterol abolished these inhibitory effects of amlodipine plus its inhibition of cell growth. Furthermore, treatment of mice with amlodipine (10 mg/kg/day × 7 days, i.p.) decreased the levels of phosphorylated EGFR in A431 xenograft tumors.SignificanceThe results indicated that amlodipine inhibits tyrosine phosphorylation of EGFR in vitro and in vivo, possibly via modulating cholesterol-rich, caveolin-1-containing membrane microdomains. |
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