Targeting Cdk5 for killing of breast cancer cells via perturbation of redox homeostasis

Reactive oxygen species (ROS) are highly reactive oxygen-containing molecules such as superoxide, hydroxyl radical, and H2O2. ROS are mainly produced as by-products during oxidative phosphorylation in mitochondria. Electron transport chain complex I generates superoxide ions toward the matrix side whereas complex III generates superoxide ions toward both the matrix and inter-membrane space. Superoxide ions are then converted into hydrogen peroxide (H2O2) by superoxide dismutase (SOD) and subsequently transformed into H2O by glutathione peroxidase. ROS play a key role in regulating numerous cellular processes, including cell growth and differentiation, phagocytosis and cell death. Thus, cellular ROS level is tightly controlled by ‘redox homeostasis’, which achieves balance by controlling ROS level through elimination via anti-oxidants [1]. Perturbation of redox homeostasis towards excess ROS brings about serious consequences such as ROS induced-irreversible oxidative damage to cellular building blocks that could trigger cell death [2]. Interestingly, it has been shown that rapidly growing and metabolically altered cancer cells have increased ROS levels compared to adjacent normal cells [1], putting cancer cells at a higher risk of reaching the threshold for ROS to instigate cell death, and thus, the implication that induction of further ROS insult in cancer cells may be utilized to kill cancer cells [1]. Our previous analysis of publicly available multiple microarray datasets that measured levels of cyclindependent kinase 5 (Cdk5) in cancer vs corresponding normal tissues showed considerable upregulation of Cdk5 level in breast cancer [3]. Recently, we found that loss of Cdk5 in breast cancer cells causes intracellular ROS increase [4], suggesting that Cdk5 could potentially be an ideal target for triggering ROS increase in breast cancer cells. Specifically, we demonstrated that Cdk5 loss in the ER+ MCF-7, HER2+ SKBR3 and triple negative MDA MB-231 breast cancer cells causes ROS increase in both mitochondria and cytoplasm and this is accompanied Editorial