Program

PO1-8-17

Ca2+-activated K+ channel KCa2.2 as a possible therapeutic target for androgen-sensitive prostate cancer

[Speaker] Satomi Niwa:1
[Co-author] Yuki Kobayashi:1, Anowara Khatun:1, Taku Naiki:2,3, Takahiro Yasui:2, Satoru Takahashi:3, Masanori Fujii:1, Susumu Ohya:1,4
1:Department of Pharmacology, Kyoto Pharmaceutical University, Japan, 2:Department of Nephro-urology, Graduate School of Medical Sciences, Nagoya City University, Japan, 3:Department of Experimental Pathology & Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Japan, 4:Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Japan

Androgens regulate the normal development and maintenance of the prostate through AR, which plays an important role in the initiation and progression of prostate cancer (PCa). Therefore, androgen deprivation (castration) therapy and anti-androgens have become standard treatments for metastatic and aggressive PCa. Yet, these therapies are limited by the inevitable onset of castration-resistant PCa (CRPC). A novel therapies are desired for the invalid castration therapies of the advanced PCa. Ca2+ -activated K+ channels (KCa) are key molecules in cancer progression and are considered to be potential targets for cancer therapy. To clarify the functional role of KCa in PCa, we examined the molecular identification of KCa subtypes in several human prostate cancer cell lines such as LNCaP, PC-3, and DU145, as well as human PCa tissues using a quantitative, real-time PCR and western blot assays. They revealed the predominant expression of KCa2.2 in androgen-sensitive LNCaP and VCaP cells but not in androgen-insensitive PC-3 and DU145 cells. In whole-cell patch clamp recordings, the Ca2+-activated K+ channels blocker, UCL1684-sensitive K+ currents were observed in LNCaP cells. Also, UCL1684 inhibited the store-operated Ca2+ entry (SOCE) in LNCaP cells. The pharmacological or siRNA-mediated inhibition of AR decreased KCa2.2 expression levels in LNCaP cells, whereas the UCL1684-induced inhibition of KCa2.2 activity did not affect AR expression levels, suggesting that KCa2.2 is a downstream effector of androgen signaling in LNCaP cells. In addition, the expression level of KCa2.2 was decreased by the short-term cultivation with a castrated medium for three to five days. However, it was recovered by the long-term castration for more than a month. Our results suggested that KCa2.2 might play an important role in the maintenance of Ca2+ influx via SOCE and might be a possible therapeutic candidate for advanced PCa.
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