erastin and Brain-Neoplasms

Ferroptosis, as an new form of non-apoptotic regulated cell death, plays an important role in human cancers. Although it is reported that HSP27 is an novel regulator of ferroptosis in cancer, it remains unknown how HSP27 affects ferroptosis in glioma. In this study, we examined the effect of HSP27 on the ferroptosis of glioblasotma. HSP27 overexpression protects glioblastoma cells from erastin-induced ferroptosis while HSP27 depletion promotes erastin-induced ferroptosis of glioblastoma. Notably, HSP27 phosphorylation is required for the protective function of HSP27 in erastin-induced ferroptosis. Overall, our study reveal novel molecular mechanisms of ferroptosis in glioma and also identify HSP27 as a negative regulator of ferroptosis and a potential target for the treatment of glioma.

Topics: Brain Neoplasms; Cell Line, Tumor; Ferroptosis; Gene Expression; Glioblastoma; HSP27 Heat-Shock Proteins; Humans; Molecular Targeted Therapy; Phosphorylation; Piperazines

Glioblastoma multiforme (GBM) is one of the most common encephalic malignant tumors. Due to a high recurrence rate and a lack of effective treatments, the average survival rate remains low. Temozolomide (TMZ), a class of alkylating agent, is widely used as a first-line therapeutic drug during the adjuvant treatment for GBM patients. However, most patients exhibit a palpable resistance to TMZ treatment. Additionally, the underlying mechanism remains to be clarified. In this study, glutathione (GSH) and reactive oxygen species (ROS) levels were found to be closely associated with the sensitivity of GBM cells to TMZ. We also found that TMZ markedly induced xCT, the subunit of glutamate/cystine transporter system xc- expression, which together with the GSH synthesis was increased while the TMZ-inducible ROS level was decreased in GBM cells. In addition, the cystathionine γ-lyase (CTH) acivity, a key enzyme in the transsulfuration pathway was enhanced by TMZ, which insured a cysteine supply and GSH synthesis in a compensatory manner when xCT was blocked. Thus, the individual inhibition of xCT by siRNA and a pharmacological inhibitor (sulfasalazine) only partially inhibited GSH synthesis and moderately enhanced the GBM cell sensitivity to TMZ. However, the TMZ‑induced cytotoxicity was markedly increased along with a marked decrease in GSH levels as result of co-treatment with erastin, which inhibited cysteine uptake from xCT transporter and suppressed CTH activity, leading to impaired transformation from methionine to cysteine. In conclusion, to GBM therapy with a drug combination of TMZ and erastin may be beneficial.

Topics: Amino Acid Transport System y+; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biological Transport; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Cystathionine gamma-Lyase; Cysteine; Dacarbazine; Drug Resistance, Neoplasm; Enzyme Activation; Glioblastoma; Glutathione; Humans; NF-E2-Related Factor 2; Piperazines; Reactive Oxygen Species; RNA Interference; RNA, Small Interfering; Sulfasalazine; Temozolomide