Abstract
Glioblastoma (GBM) represents the most common and lethal primary malignant brain tumor. The standard treatment for glioblastoma patients involves surgical resection with concomitant radio and chemotherapy. Despite today’s clinical protocol, the prognosis for patients remains very poor with a median survival of 15 months. Tumor resistance and recurrence is strongly correlated with a subpopulation of highly radioresistant and invasive cells termed Glioblastoma Stem Cells (GSCs). The transcription factor STAT3 has been found to be constitutively activated in different tumors including GBM and enhanced tumor radioresistance. In this study, we assessed radiosensitization of GSC lines isolated from patients by inhibition of STAT3 activation using Stattic or WP1066. We showed that inhibitor treatment before cell irradiation decreased the surviving fraction of GSCs suggesting that STAT3 inhibition could potentiate radiation effects. Finally, we investigated STAT3 activation status on 61 GBM clinical samples and found a preferential phosphorylation of STAT3 on Serine727 (pS727). Moreover, we found that pS727 was associated with a significant lower overall patient survival and progression-free survival but not pY705. Taken together, our results suggest that pS727-STAT3 could be a potential prognostic marker and could constitute a therapeutic target to sensitize highly radioresistant GSCs.
Highlights
Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor associated with a poor prognosis
As Signal Transducer and Activator of Transcription 3 (STAT3) is strongly activated in several cancer cell types [46–48], we compared STAT3 activation in our Glioblastoma Stem Cells (GSCs) with normal human Neural Stem Cells (H9-hNSC)
As STAT3 is a key player in GSC proliferation and self-renewal, we examined the effect of its inhibition on GSC viability by MTS assay
Summary
Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor associated with a poor prognosis. Surgical resection followed by concomitant radiochemotherapy constitutes the gold standard treatment for glioblastoma patients [1] Despite this intensive clinical protocol, the prognosis for patients remains very poor with a median survival of 15 months according to tumor radio- and chemo-resistance [2]. In 2009, Sherry et al have shown for the first time that STAT3 was required for proliferation and maintenance of multipotency in GSCs [19] This member of STAT (Signal Transducer and Activator of Transcription) family can be activated by various cytokines and growth factors like IL-6 and EGF as well as by oncogenic proteins such as Src and Ras [20–23]. Ouedraogo et al have shown that STAT3 inhibition by Gö6976 leads to radiosensitization of human conventional GBM cell lines [14] In this present work, we assessed radiosensitization of patient-derived GSC lines by specific inhibition of STAT3 phosphorylation using Stattic, a small non-peptidic inhibitor of SH2 domain and using WP1066 preventing downstream activation of STAT3 [44, 45]. We examined STAT3 phosphorylation status on 61 GBM clinical samples to evaluate the prognostic impact of pS727 and pY705
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