Glutathione reductase mediates drug resistance in glioblastoma cells by regulating redox homeostasis

Abstract

Glutathione (GSH) and GSH-related enzymes constitute the most important defense system that protects cells from free radical, radiotherapy, and chemotherapy attacks. In this study, we aim to explore the potential role and regulatory mechanism of the GSH redox cycle in drug resistance in glioblastoma multiforme (GBM) cells. We found that temozolomide (TMZ)-resistant glioma cells displayed lower levels of endogenous reactive oxygen species and higher levels of total antioxidant capacity and GSH than sensitive cells. Moreover, the expression of glutathione reductase (GSR), the key enzyme of the GSH redox cycle, was higher in TMZ-resistant cells than in sensitive cells. Furthermore, silencing GSR in drug-resistant cells improved the sensitivity of cells to TMZ or cisplatin. Conversely, the over-expression of GSR in sensitive cells resulted in resistance to chemotherapy. In addition, the GSR enzyme partially prevented the oxidative stress caused by pro-oxidant Lbuthionine -sulfoximine. The modulation of redox state by GSH or L-buthionine -sulfoximine regulated GSR-mediated drug resistance, suggesting that the action of GSR in drug resistance is associated with the modulation of redox homeostasis. Intriguingly, a trend toward shorter progress-free survival was observed among GBM patients with high GSR expression. These results indicated that GSR is involved in mediating drug resistance and is a potential target for improving GBM treatment.

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

“…Similar results were reported in clear cell renal carcinoma, where silencing the GSH biosynthesis pathway was shown to trigger ferroptosis (47). Thus, modulation of redox homeostasis by GSH/GSR appears to be an important key modulating sensitivity of cancer cells to chemotherapy (46). Interestingly, in our study, decreased levels of glutathione metabolism-related genes GSS, GSR, GPX2, IDH were observed in cells in which FZD7 was knocked down and increased expression of this signature was recorded in cells overexpressing the receptor.…”

“…Lower levels of endogenous ROS and higher levels antioxidants and GSH were found in temozolomide (TMZ)-resistant glioblastoma cells. The expression of GSR was also higher in TMZ-resistant compared to sensitive cells and silencing GSR in drug-resistant cells improved sensitivity to TMZ or cisplatin (46). Similar results were reported in clear cell renal carcinoma, where silencing the GSH biosynthesis pathway was shown to trigger ferroptosis (47).…”

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

“…Also, the treatment with NMDA along with H 2 O 2 resulted in a significant decrease in the ROS levels of cells, compared with cells exposed to H 2 O 2 alone, in both the cell lines (Figures D and E) indicating the significance or NMDAR in mitigating the ROS in presence of exogenous oxidative stress. Zhu et al () have reported that LN18 and T98G glioma cells expressed high levels of GR, whereas, LN229 and U251MG glioma cells expressed low levels of GR. Therefore, as evidenced by different studies, it can be appreciated that cell‐specific redox balance might differ due to various intrinsic factors; these effects may be attributed as an explanation for observed difference in the ROS level in two cell types used in the current study.…”

“…Cancer cells, in addition to producing high levels of ROS, are also likely to be exposed to further oxidative stress by exogenous ROS‐generating agents (Zhu et al, ). In U87MG glioma cells, a 2 h exposure to temozolomide, a DNA alkylating antineoplastic drug resulted in a twofold increase in ROS production (Zhang et al, ).…”

“…Cancer cells are metabolically active and produce high levels of reactive oxygen species (ROS) (Zhu et al, ). As highly reactive compound, ROS can lead to protein and DNA damage resulting in cellular dysfunction and death (Robert et al, ).…”