Survival of glioblastoma cells in response to endogenous and exogenous oxidative challenges: possible implication of NMDA receptor‐mediated regulation of redox homeostasis

Abstract

Cancer cells are highly metabolically active and produce high levels of reactive oxygen species (ROS). Drug resistance in cancer cells is closely related to their redox status. The role of ROS and its impact on cancer cell survival seems far from elucidation. The mechanisms through which glioblastoma cells overcome aberrant ROS and oxidative stress in a milieu of hypermetabolic state is still elusive. We hypothesize that the formidable growth potential of glioma cells is through manipulation of tumor microenvironment for its survival and growth, which can be attributed to an astute redox regulation through a nexus between activation of N-methyl-D-aspartate receptor (NMDAR) and glutathione (GSH)-based antioxidant prowess. Hence, we examined the NMDAR activation on intracellular ROS level, and cell viability on exposure to hydrogen peroxide (H 2 O 2 ), and antioxidants in glutamate-rich microenvironment of glioblastoma. The activation of NMDAR attenuated the intracellular ROS production in LN18 and U251MG glioma cells. MK-801 significantly reversed this effect. On evaluation of GSH redox cycle in these cells, the level of reduced GSH and glutathione reductase (GR) activity were significantly increased. NMDAR significantly enhanced the cell viability in LN18 and U251MG glioblastoma cells, by attenuating exogenous H 2 O 2 -induced oxidative stress, and significantly increased catalase activity, the key antioxidant that detoxifies H 2 O 2 . We hereby report an unexplored role of NMDAR activation induced protection of the rapidly multiplying glioblastoma cells against both endogenous ROS as well as exogenous oxidative challenges. We propose potentiation of reduced GSH, GR, and catalase in glioblastoma cells through NMDAR as a novel rationale of chemoresistance in glioblastoma.

NRF1 Alleviated Oxidative Stress of Glioblastoma Cells by Regulating NOR1

“…ROS can cause oxidation of DNA, proteins and lipids, as well as damage to cellular organelles, which ultimately leads to tumorigenesis when the damaged cells accumulate to a certain level (Hayes et al, 2020;Kuo et al, 2022). In our study, we found that H 2 O 2 -induced oxidative stress inhibited proliferation, migration and invasion of U251 cells and promoted cell apoptosis, which was consistent with the results of Dalavaikodihalli et al (2019). NRF1, a redox-sensitive transcription factor, is vital for maintaining healthy redox homeostasis (Yuan et al, 2018;Zhang et al, 2020).…”

Drug Resistance in Glioblastoma: The Two Faces of Oxidative Stress

“…Zhu et al ( 2018 ) demonstrated that TMZ-resistant glioma cells have higher levels of glutathione reductase (GR) and GSH than TMZ-sensitive cells. Dalavaikodihalli Nanjaiah et al ( 2019 ) showed that GSH, GR, and catalase were all up up-regulated through the glutamate-mediated activation of N-methyl-D-aspartate receptor. The expression of the amino acid antiporter that mediates the exchange of extracellular cysteine and intracellular glutamate across the plasma membrane, the system xc − , was found to be elevated in GBM cell lines, increase GSH production, mitochondrial biogenesis, oxidative phosphorylation, and ATP generation (Polewski et al, 2016 ), and conferred resistance to OS while decreasing sensitivity to TMZ.…”

Curzerene suppresses progression of human glioblastoma through inhibition of glutathione S‐transferase A4

“…Contrary to the expected results, our study showed that curzerene treatment can reduce the level of intracellular reduced GSH, which may be due to the upregulation of other intracellular oxidative stress products, such as H 2 O 2 , the consumption of GSH by the glutathione peroxidase pathway, or the direct inhibition of intracellular GSH by downregulation of GSTA4. These results further suggest that curzerene may regulate the apoptosis of glioma by changing the redox level of cells 34–36 . At the same time, the combination of curzerene and chemotherapy drugs may improve the drug sensitivity of tumor and promote the sensitivity of drug‐resistant glioma to chemotherapy drugs 37,38 …”

“…These results further suggest that curzerene may regulate the apoptosis of glioma by changing the redox level of cells. 34 , 35 , 36 At the same time, the combination of curzerene and chemotherapy drugs may improve the drug sensitivity of tumor and promote the sensitivity of drug‐resistant glioma to chemotherapy drugs. 37 , 38 …”