mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

Abstract

Radiotherapy is widely used for the treatment of cancer patients, but tumor radioresistance presents serious therapy challenges. Tumor radioresistance is closely related to high levels of mTOR signaling in tumor tissues. Therefore, targeting the mTOR pathway might be a strategy to promote solid tumor sensitivity to ionizing radiation. Radioresistance is associated with enhanced antioxidant mechanisms in cancer cells. Therefore, examination of the relationship between mTOR signaling and antioxidant mechanism-linked radioresistance is required for effective radiotherapy. In particular, the effect of mTOR signaling on antioxidant glutathione induction by the Keap1-NRF2-xCT pathway is described in this review. This review is expected to assist in the identification of therapeutic adjuvants to increase the efficacy of radiotherapy.

Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives

“…However, in a study examining the induction of autophagy by radiation and its role in the radioresistance of GSCs, the authors found that GSCs expressed lower levels of autophagy-related protein LC3 and radiation induced a low degree of autophagy in these cells [ 69 ]. Moreover, a recent study showed that autophagy induction by the mammalian targets of rapamycin (mTOR) inhibitor rapamycin triggers GSC differentiation and enhances their radiosensitization in vitro and in vivo, with rapamycin thus becoming a promising tool for radiosensitization in glioma [ 70 , 71 ].…”

Lobaplatin Enhances Radioactive 125I Seed-Induced Apoptosis and Anti-Proliferative Effect in Non-Small Cell Lung Cancer by Suppressing the AKT/mTOR Pathway

“…27 As for the resistance of radiotherapy, a review had concluded that the high expression level of mTOR is involved in antioxidant-related radioresistance of solid tumor, which indicated that mTOR pathway may be a target to promote tumor sensitivity to radiation. 28 In our previous study, through the results of iTraq and preliminary data from our previous experiments, we demonstrated that 125 I treatment significantly downregulated mTOR-related pathways in the HepG2 cell line; 20 thus, we suggested a relationship between the expression level of AKT/mTOR signaling and 125 I irradiation. In this study, we showed that 125 I treatment could indeed significantly downregulate AKT/mTOR expression.…”

Regulated Necrotic Cell Death in Alternative Tumor Therapeutic Strategies

“…Glutathione is an important molecule that regulates excessive ROS levels in the cells [ 109 ]. In particular, elevated activation of the KEAP1/NRF2/SLC7A11 axis of glutathione synthesis has been detected in various cancer cells and patients with breast cancer, bladder cancer, gastric carcinoma, glioma, and melanoma; this mechanism plays a major role in the resistance of cancer cells to cancer therapies [ 110 , 111 ]. Considering that ferroptosis is one of the types of RNCD induced by ROS-mediated lipid peroxidation process, i.e., the Fenton reaction, targeting this axis in cancer cells may be an alternative strategy for effective cancer treatment [ 112 ].…”