Mitochondrial KATP Channels Control Glioma Radioresistance by Regulating ROS-Induced ERK Activation

Abstract

Malignant glioma is the most prevalent form of malignant brain tumor. Although radiotherapy is widely used in glioma treatment, the radioresistance of glioma cells limits the success of the glioma treatment. The lack of effective targets and signaling pathways to reverse glioma radioresistance is the critical obstacle in successful treatment. In this study, we demonstrate that mitochondrial ATP-sensitive potassium channels (mtK(ATP) channels) are overexpressed in glioma cells and are closely related to the malignancy grade and the overall survival of the patients. Importantly, we showed that mtK(ATP) channels could control glioma radioresistance by regulating reactive oxygen species (ROS)-induced ERK activation. The inhibition of mtK(ATP) channels suppresses glioma radioresistance by inhibiting ERK activation both in vitro and in vivo. These findings reveal the important roles of the mitochondria and mtK(ATP) channels as key regulators in the radioresistance of glioma cells, and suggest that mtK(ATP) channel blockers and MAPK/ERK kinase (MEK) inhibitors are potential targets for drug development of glioma treatments.

Mitochondrial KATP Channel Function under Hypoxia

“…As it was shown in several studies, mKATP channels opening was capable to increase mitochondrial ROS production and trigger redox signaling mediated by PKCε [16,47,50,51]. An interplay between NOX and mitochondrial ROS, dependent on mKATP channel opening; the rise in intracellular [Ca 2+ ] c and the activation of PKCε and other signaling pathways under hypoxia (Akt, MAPK, ERK [40,41,52,53]) were shown in several works. Thus, hypoxiainduced NOX activation was shown to be dependent on mitochondrial ROS, and the suppression of ROS production by respiratory inhibitors (rotenone, myxothiazol) abolished NOX activation [42,47].…”

“…Elevated expression of mKATP channel and the channel activation that were observed under hypoxia [20,21,41,59] increase the "weight" of ATP-sensitive K + transport in the regulation of mitochondrial functions and metabolism. This is still more visible in malignant cells functioning in hypoxic environment, in which overexpression of mKATP channel was shown [53].…”

“…In the literature, it was supposed that protection of tissues against the impairments caused by hypoxia afforded by mitochondrial K + transport is largely based on bioenergetic effects of K + transport and signaling triggered by K + channels opening [16,41,50,53]. The impact of ATPsensitive K + transport on the oxygen consumption, membrane potential, ATP synthesis, Ca 2+ transport and ROS production is largely dependent on the abundance of the channel in mitochondrial membrane.…”

“…The impact of ATPsensitive K + transport on the oxygen consumption, membrane potential, ATP synthesis, Ca 2+ transport and ROS production is largely dependent on the abundance of the channel in mitochondrial membrane. Oxygen deficiency affects functional consequences of mKATP channels opening by modulating channels expression and activity [20,53,59]. As it was shown in cardiomyocytes, the activation of cardiac mKATP channels under hypoxia was mediated by the interactions of conducting subunit Kir6.2 with heat shock protein 90, HSP90 [25] and Kir6.1 with gap junction protein connexin 43 and PKCε [26].…”

“…Interestingly, both the elevation [16,41] and suppression [21,40] of ROS production were reported to improve cardiac and cardiomyocyte functions after the exposure to hypoxia in a way dependent on mKATP channel opening. Based on the published data, it is tempting to hypothesize that bidirectional regulation of ROS production by potassium transport observed in the literature could represent a flexible mechanism of the fast response to the elevation of ROS levels generally observed under hypoxia and that, dependent on conditions, could prevent ROS overproduction [57,75] or trigger ROS-dependent signaling [16,41,50,53], which makes this function of mKATP channel of especial importance under limited oxygen availability.…”