Down-Regulation of Ca ²⁺-Activated K ⁺ Channel K _Ca1.1 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 Ca ²⁺-activated K ⁺ channel K _Ca1.1 regulates intracellular Ca ²⁺ 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 K _Ca1.1 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 K _Ca1.1 transcripts and proteins in MDA-MB-453 cells, resulting in the significant inhibition of depolarization responses induced by paxilline, a specific K _Ca1.1 blocker. The specific proteasome inhibitor MG132 suppressed VDR agonist-induced decreases in K _Ca1.1 protein expression. These results suggest that K _Ca1.1 is a new downstream target of VDR signaling and the down-regulation of K _Ca1.1 through the transcriptional repression of K _Ca1.1 and enhancement of K _Ca1.1 protein degradation contribute, at least partly, to the antiproliferative effects of VDR agonists in breast cancer cells.