KV11.1 Channel Activity Control Reactive Oxygen Species (ROS) Homeostasis in Breast Cancer Cells

Abstract

Generation and control of reactive oxygen species (redox system) is essential for maintaining cellular homeostasis. Increased oxidative stress can play a critical role in a variety of pathological condition including cancer. It is known that cancer cells present higher level of DNA oxidation which is dependent of downregulation of antioxidant enzymes such as the Nuclear factor erythroid 2-related factor 2 (NRF2). This phenomenon underlies the characteristic genetic instability of cancer cells and is a feature of neoplastic lesions. Therefore, activation of antioxidant enzymes received attention as a potential anticancer strategy. However, the biochemical cascades controlling the redox system in cancer cell survival or death is not clearly understood. We discovered that activity of the Kv11.1 channel (hERG1) arrests breast cancer proliferation by activating a senescent-like phenotype that coincides with increased ROS formation. We found that stimulation of Kv11.1 channel with selective activator molecules (NS1643 or PD118057) produces a significant alteration of mitochondrial function which in turn increases ROS production. Interestingly, cancer cells respond to the Kv11.1-dependent increase of ROS by activation of the NRF2 transcription factor leading to an increased production of antioxidant proteins. Therefore, the NRF2 protein promotes cell survival. Interestingly, the combination of the Kv11.1 activator NS1643 with suppression of NRF2 function produced a significant increase of ROS which in turn leads to cell death. Our data demonstrate that activity of the Kv11.1 channel control mitochondria function and ROS formation in breast cancer cells. Remarkably, these cells activate transcription of antioxidant enzymes via NRF2 which acts as survival mechanism.