Arsenic trioxide disrupts glioma stem cells via promoting PML degradation to inhibit tumor growth

// Wenchao Zhou 1 , Lin Cheng 2 , Yu Shi 1, 3 , Susan Q. Ke 1 , Zhi Huang 1 , Xiaoguang Fang 1 , Cheng-wei Chu 1 , Qi Xie 1 , Xiu-wu Bian 3 , Jeremy N. Rich 1 , Shideng Bao 1 1 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA 2 State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China 3 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China Correspondence to: Shideng Bao, e-mail: baos@ccf.org Keywords: glioblastoma, glioma stem cell, arsenic trioxide, PML, c-Myc Received: July 23, 2015      Accepted: October 01, 2015      Published: October 14, 2015 ABSTRACT Glioblastoma multiforme (GBM) is the most lethal brain tumor. Tumor relapse in GBM is inevitable despite maximal therapeutic interventions. Glioma stem cells (GSCs) have been found to be critical players in therapeutic resistance and tumor recurrence. Therapeutic drugs targeting GSCs may significantly improve GBM treatment. In this study, we demonstrated that arsenic trioxide (As 2 O 3 ) effectively disrupted GSCs and inhibited tumor growth in the GSC-derived orthotopic xenografts by targeting the promyelocytic leukaemia (PML). As 2 O 3 treatment induced rapid degradation of PML protein along with severe apoptosis in GSCs. Disruption of the endogenous PML recapitulated the inhibitory effects of As 2 O 3 treatment on GSCs both in vitro and in orthotopic tumors. Importantly, As 2 O 3 treatment dramatically reduced GSC population in the intracranial GBM xenografts and increased the survival of mice bearing the tumors. In addition, As 2 O 3 treatment preferentially inhibited cell growth of GSCs but not matched non-stem tumor cells (NSTCs). Furthermore, As 2 O 3 treatment or PML disruption potently diminished c-Myc protein levels through increased poly-ubiquitination and proteasome degradation of c-Myc. Our study indicated a potential implication of As 2 O 3 in GBM treatment and highlighted the important role of PML/c-Myc axis in the maintenance of GSCs.