Eag and HERG potassium channels as novel therapeutic targets in cancer

Abstract

Voltage gated potassium channels have been extensively studied in relation to cancer. In this review, we will focus on the role of two potassium channels, Ether à-go-go (Eag), Human ether à-go-go related gene (HERG), in cancer and their potential therapeutic utility in the treatment of cancer. Eag and HERG are expressed in cancers of various organs and have been implicated in cell cycle progression and proliferation of cancer cells. Inhibition of these channels has been shown to reduce proliferation both in vitro and vivo studies identifying potassium channel modulators as putative inhibitors of tumour progression. Eag channels in view of their restricted expression in normal tissue may emerge as novel tumour biomarkers.

Figure 1

Potential mechanisms of malignant transformation by K⁺ channels. Increased expression of K⁺ channels on cell membrane results in increased influx of Ca²⁺ ions resulting in increased transition of cells through G1/S phase of cell cycle. The channels in presence of hypoxia lead to release of HIF1 and VGEF factor leading to increased angiogenesis and subsequent invasion and metastasis of tumours. The nuclear localisation sequence (NLS) in the C terminus on activation results in perinuclear localisation of the channel leading to activation of Mitogen activated protein kinase (MARP) pathway resulting in increased cell proliferation. The Eag channels also act through the Ca calmodulin pathway to activate cell proliferation.