Pharmacological separation of hEAG and hERG K+ channel function in the human mammary carcinoma cell line MCF-7.
Pharmacological inhibitors of the human ether-a-go-go (hEAG) potassium channel, astemizole and imipramine, have been used to demonstrate that hEAG plays a role in cancer cell proliferation. Astemizole and imipramine are, however, relatively non-specific ion channel blockers, as astemizole can also block the related potassium channel, human ether-a-go-go-related (hERG). Therefore, we aimed to determine the molecular target of astemizole, in the human mammary carcinoma cell line MCF-7. We initially confirmed the expression of KCNH1 and KCNH2 mRNA and hEAG and hERG channel protein in MCF-7 cells. Using a [3H]-thymidine incorporation assay we determined that astemizole inhibited MCF-7 cell proliferation, whereas the hERG-specific channel blocker E-4031 had no effect. We then determined that E-4031 inhibited the regulatory volume decrease (RVD) observed in these cells following exposure to hypotonic solutions, confirming that functional hERG channels are present and may be important for cell volume regulation in MCF-7 cells. Our results suggest, for the first time, that hERG is involved in cell volume regulation. In addition, the function of hEAG and hERG in MCF-7 cell proliferation can be separated pharmacologically by utilizing the channel inhibitors astemizole and E-4031. The hEAG channel function in MCF-7 cells appears to be involved in the regulation of cell proliferation, whereas hERG is involved in cell volume regulation.
Roy
Jeremy
J
Department of Physiology and Biophysics, Faculty of Medicine, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, NS, Canada. jwroy@dal.ca
Vantol
Brenna
B
Cowley
Elizabeth A
EA
Blay
Jonathan
J
Linsdell
Paul
P
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018926:Anti-Allergic Agents / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D016589:Astemizole / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D008133:Long QT Syndrome; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D018926:Anti-Allergic Agents; D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; C000606913:KCNH2 protein, human; D010880:Piperidines; D011725:Pyridines; D012333:RNA, Messenger; C063968:E 4031; D016589:Astemizole; D007099:Imipramine