Potassium ion (K+) channels are a highly diverse class of membrane ion channels. K+ channels regulate many cellular functions such as membrane excitability, solute and water transport, changes in cell-volume, adhesion, motility, apoptosis, proliferation and metabolic activity. The voltage-gated K+ channel (Kv) superfamily is divided into Shaker and ether-a-go-go families. We have examined, by immunohistochemistry, the expression of two voltage-gated K+ channels, Kv1.3 (a Shaker-type channel) and human ether-a-go-go-related gene (HERG, Kv11.1). Strong Kv1.3 and HERG immunostaining was observed in normal human prostate and benign prostatic hyperplasia (BPH) specimens. In contrast, Kv1.3 and HERG expression was frequently down-regulated in human prostate cancer. Reduced Kv channel activity was associated with chemoresistance. In preliminary studies, inhibition of Kv1.3 activity in human prostate cell lines, using a Kv1.3-selective channel- blocker, resulted in increased expression of known markers of cancer progression.
The specific aims of the proposal are to 1) determine the relationships between Kv1.3 and HERG immunostaining levels in clinical prostate cancer specimens and clinicopathological characteristics such as patient age, tumor grade, stage, PSA recurrence and survival status;2) examine the expression of the two Kv channels in six human prostate cell lines by RT-PCR and Western blotting;3) examine the effect of Kv1.3 and HERG blockade on cellular proliferation/apoptosis and chemoresistance (using fluorescent dyes), on cellular invasiveness (using a modified Boyden chamber assay) as well as on the cellular expression of cytokines and cell adhesion molecules (by immunoblotting). These studies will provide an understanding of the role of Kv1.3 and HERG in human prostate cells and in prostate cancer progression. New biomarkers of prostate cancer progression are urgently needed to avoid unnecessary treatment, to predict outcome and to develop more effective treatment strategies. The two Kv channels, alone or in combination, could prove to be useful tumor markers.
In patients with localized prostate cancer, new biomarkers are needed to identify patients who need aggressive treatment. Levels of Kv1.3 and/or HERG expression, in prostate biopsies or resected tissue, could be useful both in diagnosis and in prognosis of prostate cancer. The proposed studies will provide an understanding of Kv1.3 and HERG channel activity in human prostate cells and in prostate cancer progression, which is essential for their development as clinically useful tumor markers.
