Abstract

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.

Original languageEnglish
Pages (from-to)69961-69975
Number of pages15
JournalOncotarget
Volume7
Issue number43
DOIs
Publication statusPublished - 2016

Fingerprint

Glioma
Carcinogenesis
Stem Cells
Phenotype
Agammaglobulinaemia tyrosine kinase
PCI 32765
Tissue Array Analysis
Therapeutics
Neoplasms
Brain
Glioblastoma
Computational Biology
Heterografts
Ovarian Neoplasms
Prostatic Neoplasms
B-Lymphocytes
Down-Regulation
Biomarkers
Radiation
Staining and Labeling

Keywords

  • Bruton's tyrosine kinase
  • Cancer stem cells
  • Glioma
  • Ibrutinib

ASJC Scopus subject areas

  • Oncology

Cite this

Preclinical investigation of ibrutinib, a Bruton's kinase tyrosine (Btk) inhibitor, in suppressing glioma tumorigenesis and stem cell phenotypes. / Wei, Li; Su, Yu Kai; Lin, Chien Min; Chao, Tsu Yi; Huang, Shang Pen; Huynh, Thanh Tuan; Jan, Hsun Jin; Whang-Peng, Jacqueline; Chiou, Jeng Fong; Wu, Alexander T H; Hsiao, Michael.

In: Oncotarget, Vol. 7, No. 43, 2016, p. 69961-69975.

Research output: Contribution to journalArticle

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AU - Chao, Tsu Yi

AU - Huang, Shang Pen

AU - Huynh, Thanh Tuan

AU - Jan, Hsun Jin

AU - Whang-Peng, Jacqueline

AU - Chiou, Jeng Fong

AU - Wu, Alexander T H

AU - Hsiao, Michael

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