Overcoming chemo-resistance of pediatric ependymoma by inhibition of STAT3 signaling

Abstract

Introduction: The long-term clinical outcome of pediatric intracranial epepdymoma is poor with high rate of recurrence. One of the main reasons for this poor outcome is the tumors inherent resistance to chemotherapy. Signal tranducer and activator of transcription 3 (STAT3) is overactive in many human cancers, and inhibition of STAT3 signaling is an emerging area of interest in oncology. In this study, the possibility of STAT3 inhibition as a treatment was investigated in pediatric intracranial ependymoma tissues and cell lines. Methods: STAT3 activation status was checked in ependymoma tissues. The responses to conventional chemotherapeutic agents and a STAT3 inhibitor, WP1066 in primarily cultured ependymoma cells were measured by cell viability assay. Apoptosis assays were conducted to reveal the cytotoxic mechanism of applied agents. The change of STAT3 signaling after WP1066 treatment was evaluated. Results: High levels of phospho-STAT3 (p-STAT3) expression were observed in ependymoma tissue, especially in the anaplastic histology group. There was no cytotoxic effect of cisplatin, ifosfamide, and etoposide. Both brain tumor-initiating cells (BTICs) and bulk tumor cells (BCs) showed considerably decreased viability after WP1066 treatment. However, BTICs had fewer responses than BCs. No additive or synergistic effect was observed for combination therapy of WP1066 and cisplatin. Robust apoptosis was observed after WP1066 treatment. BTICs of other brain tumors also activated STAT3 and WP1066 effectively abrogated p-STAT3 expression. Increase of the interleukin-6 receptor (IL-6R) was observed after WP1066 treatment. Conclusions: In this study, we observed a cytotoxic effect of STAT3 inhibitor on ependymoa BTICs and BCs. There is urgent need to develop new therapeutic agents for pediatric ependymoma. STAT3 inhibitors may be a new group of drugs for clinical application.