title: Down-Regulation of Ca2+-Activated K⁺ Channel KCa1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists.
abstract: Vitamin D (VD) reduces the risk of breast cancer and improves disease prognoses. Potential VD analogs are being developed as therapeutic agents for breast cancer treatments. The large-conductance Ca2+-activated K⁺ channel KCa1.1 regulates intracellular Ca2+signaling pathways and is associated with high grade tumors and poor prognoses. In the present study, we examined the effects of treatments with VD receptor (VDR) agonists on the expression and activity of KCa1.1 in human breast cancer MDA-MB-453 cells using real-time PCR, Western blotting, flow cytometry, and voltage-sensitive dye imaging. Treatments with VDR agonists for 72 h markedly decreased the expression levels of KCa1.1 transcripts and proteins in MDA-MB-453 cells, resulting in the significant inhibition of depolarization responses induced by paxilline, a specific KCa1.1 blocker. The specific proteasome inhibitor MG132 suppressed VDR agonist-induced decreases in KCa1.1 protein expression. These results suggest that KCa1.1 is a new downstream target of VDR signaling and the down-regulation of KCa1.1 through the transcriptional repression of KCa1.1 and enhancement of KCa1.1 protein degradation contribute, at least partly, to the antiproliferative effects of VDR agonists in breast cancer cells.
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan. anowarakhatun07@gmail.com.
authors.forename: Anowara
authors.initials: A
authors.lastname: Khatun
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan. ky13291@poppy.kyoto-phu.ac.jp.
authors.forename: Mayu
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan. kito@mb.kyoto-phu.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kito
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan. sniwa@mb.kyoto-phu.ac.jp.
authors.forename: Satomi
authors.initials: S
authors.lastname: Niwa
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 403-8334, Japan. suzukit@koto.kpu-m.ac.jp.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan. sohya@mb.kyoto-phu.ac.jp.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohya
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002117:Calcitriol / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000378:metabolism
chemical_list: C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D007976:Leupeptins; D009363:Neoplasm Proteins; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; C055085:calcipotriene; D002117:Calcitriol; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: K+ channel; KCa1.1; breast cancer; protein degradation; transcription; vitamin D receptor