Potassium Channel Blockage and Invasiveness of Strongly Metastatic Prostate and Breast Cancer Cells

Background: Voltage-gated sodium channels (VGSCs) are upregulated during cancer progression and promote metastatic cell behaviors. In contrast, voltage-gated potassium channels (VGPCs) that control proliferation, among other roles, are downregulated. In this study, we tested the effects of blocking VGPCs on the Matrigel invasiveness specifically of strongly metastatic cancer cells. Materials and Methods: The rat prostate cancer Mat-LyLu cell line and the human breast cancer MDA-MB-231 cell line, both strongly metastatic and expressing functional VGSCs, were adopted as models. Matrigel invasion assays and patch-clamp electrophysiology were used to monitor pharmacological effects of VGPC blockage. Results: Margatoxin (MGTX) significantly suppressed the outward currents in Mat-LyLu cells, consistent with K(v)1.3 being the predominant VGPC in these cells. For the MDA-MB-231 cells, 4-aminopyridine (4-AP) was used as a general blocker of VGPCs. Treatment with the respective blocker significantly increased the cellular invasiveness under conditions wherein proliferative activity was not affected. As expected, invasiveness was reduced by treating the cells with the VGSC blocker tetrodotoxin (TTX). Importantly, the proinvasive effect of MGTX was suppressed completely by cotreating the MDA-MB-231 cells with TTX. Conclusions: (1) VGPC blockage promotes invasiveness in strongly metastatic carcinoma cell lines and this is associated with functional VGSC expression well known to occur in such cells. (2) The available data taken together are supportive of the Celex Hypothesis, proposing that the electrical excitability of cancer cells (resulting from functional VGSC upregulation and concomitant VGPC downregulation) promotes metastatic invasiveness.