Dual blockage of STAT3 and ERK1/2 eliminates radioresistant GBM cells
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 Li
Affiliations
Bowen Xie
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China; Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA, 95817, USA
Lu Zhang
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China; Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA, 95817, USA
Wenfeng Hu
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China
Ming Fan
Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA, 95817, USA
Nian Jiang
Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA, 95817, USA
Yumei Duan
Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
Di Jing
Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA, 95817, USA
Wenwu Xiao
Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, CA, USA; NCI-Designated Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA
Ruben C. Fragoso
Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA, 95817, USA; NCI-Designated Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA
Kit S. Lam
Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, CA, USA; NCI-Designated Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA
Lun-Quan Sun
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China; Corresponding author. Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
Jian Jian Li
Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, CA, 95817, USA; NCI-Designated Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA; Corresponding author. Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, USA.
Radiotherapy (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 inhibition of ERK1/2 and STAT3 remarkably eliminates resistant GBM cells and inhibits tumor regrowth. These findings demonstrate a previously unknown feature ofSTAT3-mediated ERK1/2 regulation and an effective combination of two targets in resensitizing GBM to RT. Keywords: GBM, Radiotherapy, Radioresistance, STAT3, ERK1/2, Tumor regrowth
