Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function

  • Authors:
    • Liangyu Chen
    • Xinxing Li
    • Libo Liu
    • Bo Yu
    • Yixue Xue
    • Yunhui Liu
  • View Affiliations

  • Published online on: January 13, 2015     https://doi.org/10.3892/or.2015.3712
  • Pages: 1465-1474
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Abstract

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.
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March-2015
Volume 33 Issue 3

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Chen L, Li X, Liu L, Yu B, Xue Y and Liu Y: Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function. Oncol Rep 33: 1465-1474, 2015.
APA
Chen, L., Li, X., Liu, L., Yu, B., Xue, Y., & Liu, Y. (2015). Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function. Oncology Reports, 33, 1465-1474. https://doi.org/10.3892/or.2015.3712
MLA
Chen, L., Li, X., Liu, L., Yu, B., Xue, Y., Liu, Y."Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function". Oncology Reports 33.3 (2015): 1465-1474.
Chicago
Chen, L., Li, X., Liu, L., Yu, B., Xue, Y., Liu, Y."Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function". Oncology Reports 33, no. 3 (2015): 1465-1474. https://doi.org/10.3892/or.2015.3712