TY - JOUR
T1 - The intermediate conductance Ca 2+-activated K + channel inhibitor TRAM-34 stimulates proliferation of breast cancer cells via activation of oestrogen receptors
AU - Roy, J. W.
AU - Cowley, E. A.
AU - Blay, J.
AU - Linsdell, P.
PY - 2010/2
Y1 - 2010/2
N2 - 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 K v10.1 and K Ca3.1 K + channels suppressed basal proliferation of MCF-7 cells, but not oestrogen-stimulated proliferation. TRAM-34, a specific inhibitor of K Ca3.1 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 K v10.1 and K Ca3.1 play a role in basal, but not oestrogen-stimulated MCF-7 cell proliferation. TRAM-34, as well as inhibiting K Ca3.1, 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.
AB - 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 K v10.1 and K Ca3.1 K + channels suppressed basal proliferation of MCF-7 cells, but not oestrogen-stimulated proliferation. TRAM-34, a specific inhibitor of K Ca3.1 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 K v10.1 and K Ca3.1 play a role in basal, but not oestrogen-stimulated MCF-7 cell proliferation. TRAM-34, as well as inhibiting K Ca3.1, 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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U2 - 10.1111/j.1476-5381.2009.00557.x
DO - 10.1111/j.1476-5381.2009.00557.x
M3 - Article
C2 - 20050851
AN - SCOPUS:76449104454
SN - 0007-1188
VL - 159
SP - 650
EP - 658
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 3
ER -