The intermediate conductance Ca2+-activated K+ channel inhibitor TRAM-34 stimulates proliferation of breast cancer cells via activation of oestrogen receptors |
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Authors: | JW Roy EA Cowley J Blay P Linsdell |
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Institution: | 1.Department of Physiology and Biophysics, Dalhousie University, Halifax, Canada;2.Departments of Pharmacology, Pathology and Biology, Dalhousie University, Halifax, Canada |
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Abstract: | Background and purpose:K+ channels play a role in the proliferation of cancer cells. We have investigated the effects of specific K+ channel inhibitors on basal and oestrogen-stimulated proliferation of breast cancer cells.Experimental approach:Using the mammary adenocarcinoma cell line MCF-7 we assayed cell proliferation by radiolabelled thymidine incorporation in the absence or presence of various K+ channel inhibitors with or without 17β-oestradiol.Key results:Inhibitors of Kv10.1 and KCa3.1 K+ channels suppressed basal proliferation of MCF-7 cells, but not oestrogen-stimulated proliferation. TRAM-34, a specific inhibitor of KCa3.1 channels increased or decreased cell proliferation depending on the concentration. At intermediate concentrations (3–10 µM) TRAM-34 increased cell proliferation, whereas at higher concentrations (20–100 µM) TRAM-34 decreased cell proliferation. The enhancement of cell proliferation caused by TRAM-34 was blocked by the oestrogen receptor antagonists ICI182,780 and tamoxifen. TRAM-34 also increased progesterone receptor mRNA expression, decreased oestrogen receptor-α mRNA expression and reduced the binding of radiolabelled oestrogen to MCF-7 oestrogen receptor, in each case mimicking the effects of 17β-oestradiol.Conclusions and implications:Our results demonstrate that K+ channels Kv10.1 and KCa3.1 play a role in basal, but not oestrogen-stimulated MCF-7 cell proliferation. TRAM-34, as well as inhibiting KCa3.1, directly interacts with the oestrogen receptor and mimics the effects of 17β-oestradiol on MCF-7 cell proliferation and gene modulation. Our finding that TRAM-34 is able to activate the oestrogen receptor suggests a novel action of this supposedly specific K+ channel inhibitor and raises concerns of interpretation in its use. |
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Keywords: | TRAM-34 oestrogen potassium channel proliferation MCF-7 cancer |
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