Preclinical investigation of ibrutinib, a Bruton’s kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes
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Li Wei1,2,3, Yu-Kai Su3, Chien-Min Lin3,4, Tsu-Yi Chao5, Shang-Pen Huang5,6, Thanh-Tuan Huynh7, Hsun-Jin Jan8, Jacqueline Whang-Peng9, Jeng-Fong Chiou10,11, Alexander T.H. Wu1, Michael Hsiao12,13
1The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan
2Division of Neurosurgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
3Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
4Division of Neurosurgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
5Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
6Department of Neurology, Taiwan Adventist Hospital, Taipei, Taiwan
7Center for Molecular Biomedicine, University of Medicine and Pharmacy, HoChiMinh City, Vietnam
8The Department of Medical Laboratory and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan
9Division of Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan
10Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan
11Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
12Genomics Research Center, Academia Sinica, Taipei, Taiwan
13Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Alexander T.H. Wu, email: [email protected]
Michael Hsiao, email: [email protected]
Keywords: glioma, cancer stem cells, Bruton’s tyrosine kinase, ibrutinib
Received: March 24, 2016 Accepted: August 10, 2016 Published: August 24, 2016
Standard interventions for glioma include surgery, radiation and chemotherapies but the prognosis for malignant cases such as glioblastoma multiforme remain grim. Even with targeted therapeutic agent, bevacitumab, malignant glioma often develops resistance and recurrence. Thus, developing alternative interventions (therapeutic targets, biomarkers) is urgently required. Bruton’s tyrosine kinase (Btk) has been long implicated in B cell malignancies but surprisingly it has recently been shown to also play a tumorigenic role in solid tumors such as ovarian and prostate cancer. Bioinformatics data indicates that Btk is significantly higher in clinical glioma samples as compared to normal brain cells and Btk expression level is associated with stage progression. This prompts us to investigate the potential role of Btk as a therapeutic target for glioma. Here, we demonstrate Btk expression is associated with GBM tumorigenesis. Down-regulation of Btk in GBM cell lines showed a significantly reduced abilities in colony formation, migration and GBM sphere-forming potential. Mechanistically, Btk-silenced cells showed a concomitant reduction in the expression of CD133 and Akt/mTOR signaling. In parallel, Ibrutinib (a Btk inhibitor) treatment led to a similar anti-tumorigenic response. Using xenograft mouse model, tumorigenesis was significantly reduced in Btk-silenced or ibrutinib-treated mice as compared to control counterparts. Finally, our glioma tissue microarray analysis indicated a higher Btk staining in the malignant tumors than less malignant and normal brain tissues. Collectively, Btk may represent a novel therapeutic target for glioma and ibrunitib may be used as an adjuvant treatment for malignant GBM.
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