Abstract
BackgroundOxidative stress enhances tumor invasion and metastasis in brain cancer. The activation of divalent metal transporter 1 (DMT1), which is regulated by glutamate receptors, can result in the increase of oxidative stress and risk of cancer development. Propofol, an anesthetic with antioxidant capacity, has been shown to decrease oxidative stress in several different types of cancer. However, the underlying mechanism remains unclear. Therefore, the present study aimed to elucidate the mechanism underlying the suppression of oxidative stress in glioma cells by propofol. It was hypothesized that propofol may inhibit oxidative stress in gliomas via suppressing Ca2+-permeable α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA) receptor (CPAR)-DMT1 signaling.MethodsMale Wistar rats with C6 gliomas, which were established by intracranial injection of C6 glioma cells, were either treated with propofol or not for 6 h before being sacrificed. The levels of AMPA receptor subunit GluR2 and DMT1 protein expression were assessed using western blotting. The association between CPARs and DMT1 was confirmed in vitro using the AMPA receptor activator (R, S)-AMPA. Glutathione and reactive oxygen species assay kits were used to evaluate tumor oxidative stress. The effect of propofol on glioma proliferation was evaluated by determining tumor weight, cell cycles and a growth curve.ResultsPropofol infusion at either 20 or 40 mg/kg-1/h-1 increased GluR2 levels and downregulated DMT1 expression as well as glutathione content markedly in the periphery compared with that in the glioma core. The in vitro results revealed that (R, S)-AMPA increased DMT1 expression and reactive oxygen species levels, which were partly reversed by propofol treatment.ConclusionPropofol regulated DMT1 expression by modulating CPARs, resulting in the inhibition of tumor oxidative stress and glioma growth. The present study provides evidence for optimizing the selection of anesthetic drugs in perioperative management and prognosis of patients with glioma.
Highlights
Of tumors in the central nervous system, >70% are gliomas, originating from astrocytes, oligodendrocytes and ependymal cells [1]
The present study revealed propofol anti-tumor effect from the perspective of oxidative stress inhibition in glioma cells through regulating divalent metal transporter 1 (DMT1) expression by modifying Ca2+-permeable AMPA receptors (CPARs)
The results of the present study show that propofol inhibits oxidative stress and DMT1 expression and eventually downregulates GSH and reactive oxygen species (ROS) production, which disrupts the energy supply required for tumor growth and metabolism (Figure 7)
Summary
Of tumors in the central nervous system, >70% are gliomas, originating from astrocytes, oligodendrocytes and ependymal cells [1]. An increasing number of studies have revealed that improper selection of anesthetics or anesthesia can adversely affect the prognosis of patients with glioma [3, 4]. Large amounts of evidence have confirmed that propofol inhibit the proliferation, invasion and migration, and facilitate apoptosis of tumor cells of various tissue origins, such as lung, gastrointestinal tract, pancreas, ovarian and cervical cancer [5,6,7,8,9]. The mechanism underlying the effect of propofol in tumors, gliomas, remains largely unknown. An anesthetic with antioxidant capacity, has been shown to decrease oxidative stress in several different types of cancer. The present study aimed to elucidate the mechanism underlying the suppression of oxidative stress in glioma cells by propofol. It was hypothesized that propofol may inhibit oxidative stress in gliomas via suppressing Ca2+-permeable a-amino3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA) receptor (CPAR)-DMT1 signaling
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