Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor

W. Guo, R. Liu, G. Bhardwaj, J. C. Yang, C. Changou, A. H. Ma, A. Mazloom, S. Chintapalli, K. Xiao, W. Xiao, P. Kumaresan, E. Sanchez, C. T. Yeh, C. P. Evans, R. Patterson, K. S. Lam, H. J. Kung

研究成果: 雜誌貢獻文章同行評審

34 引文 斯高帕斯(Scopus)

摘要

Btk and Etk/BMX are Tec-family non-receptor tyrosine kinases. Btk has previously been reported to be expressed primarily in B cells and has an important role in immune responses and B-cell malignancies. Etk has been shown previously to provide a strong survival and metastasis signal in human prostate cancer cells, and to confer androgen independence and drug resistance. While the role of Etk in prostate carcinogenesis is well established, the functions of Btk in prostate cancer have never been investigated, likely due to the perception that Btk is a hematopoietic, but not epithelial, kinase. Herein, we found that Btk is overexpressed in prostate cancer tissues and prostate cancer cells. The level of Btk in prostate cancer tissues correlates with cancer grades. Knockdown of Btk expression selectively inhibits the growth of prostate cancer cells, but not that of the normal prostate epithelial cells, which express very little Btk. Dual inhibition of Btk and Etk has an additive inhibitory effect on prostate cancer cell growth. To explore Btk and Etk as targets for prostate cancer, we developed a small molecule dual inhibitor of Btk and Etk, CTN06. Treatment of PC3 and other prostate cancer cells, but not immortalized prostate epithelial cells with CTN06 resulted in effective cell killing, accompanied by the attenuation of Btk/Etk signals. The killing effect of CTN06 is more potent than that of commonly used inhibitors against Src, Raf/VEGFR and EGFR. CTN06 induces apoptosis as well as autophagy in human prostate cancer cells, and is a chemo-sensitizer for docetaxel (DTX), a standard of care for metastatic prostate cancer patients. CTN06 also impeded the migration of human prostate cancer cells based on a 'wound healing' assay. The anti-cancer effect of CTN06 was further validated in vivo in a PC3 xenograft mouse model.
原文英語
文章編號e1409
期刊Cell Death and Disease
5
發行號9
DOIs
出版狀態已發佈 - 1月 1 2014

ASJC Scopus subject areas

  • 細胞生物學
  • 免疫學
  • 癌症研究
  • 細胞與分子神經科學

指紋

深入研究「Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor」主題。共同形成了獨特的指紋。

引用此