Dual blockage of STAT3 and ERK1/2 eliminates radioresistant GBM cells

Publication date: Available online 9 April 2019Source: Redox BiologyAuthor(s): Bowen Xie, Lu Zhang, Wenfeng Hu, Ming Fan, Nian Jiang, Yumei Duan, Di Jing, Wenwu Xiao, Ruben C. Fragoso, Kit S. Lam, Lun-Quan Sun, Jian Jian LiAbstractRadiotherapy (RT) is the major modality for control of glioblastoma multiforme (GBM), the most aggressive brain tumor in adults with poor prognosis and low patient survival rate. To improve the RT efficacy on GBM, the mechanism causing tumor adaptive radioresistance which leads to the failure of tumor control and lethal progression needs to be further elucidated. Here, we conducted a comparative analysis of RT-treated recurrent tumors versus primary counterparts in GBM patients, RT-treated orthotopic GBM tumors xenografts versus untreated tumors and radioresistant GBM cells versus wild type cells. The results reveal that activation of STAT3, a well-defined redox-sensitive transcriptional factor, is causally linked with GBM adaptive radioresistance. Database analysis also agrees with the worse prognosis in GBM patients due to the STAT3 expression-associated low RT responsiveness. However, although the radioresistant GBM cells can be resensitized by inhibition of STAT3, a fraction of radioresistant cells can still survive the RT combined with STAT3 inhibition or CRISPR/Cas9-mediated STAT3 knockout. A complementally enhanced activation of ERK1/2 by STAT3 inhibition is identified responsible for the survival of the remaining resistant tumor cells. Dual ...
Source: Redox Biology - Category: Biology Source Type: research