Voltage‐gated K+ Channels as Potential Therapeutic Targets for Lung Adenocarcinoma Therapy

Abstract

Voltage-gated K+ (Kv) channels have been considered as a regulator of membrane potential and neuronal excitability. Recently, accumulated evidence has indicated that several Kv channel subtypes contribute to the control of cell proliferation in various types of cells and are worthy of notice for emerging molecular targets of cancer therapy. In the present study, we investigated the effects of the dendrotoxinκ (DTX-κ) and margatoxin (MgTX) which are Kv1.1 and Kv1.3 specific blockers respectively on tumor formation using a xenograft model induced by the human lung adenocarcinoma cell line, A549 cells. The mRNA and protein of Kv1.1 and Kv1.3 was expressed in A549 cells and the blockade of Kv1.1 by DTX-κ or Kv1.3 by MgTX reduced the formation of tumors in nude mice. Furthermore, treatment with DTX-κ increased the protein expression of p21Waf1/Cip1, p27Kip1 and p15INK4B and significantly decreased the protein expression of cyclin D3 in tumor tissues compared to control. In addition, selective inhibition of Kv1.3 significantly increased expression level of p21Waf1/Cip1 and significantly decreased the expression level of Cdk4 and cyclin D3. These results indicate that the DTX-κ and MgTX demonstrated anti-tumor effects in A549 cells through the pathway governing G1-S transition. These results suggest that certain Kv channel blockers may serve as novel therapeutic targets for lung adenocarcinoma therapy. This work is supported by National Research Foundation of Korea (2010-0011556).