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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article numbere1409
JournalCell Death and Disease
Volume5
Issue number9
DOIs
Publication statusPublished - Jan 1 2014

Fingerprint

Prostatic Neoplasms
Prostate
docetaxel
B-Lymphocytes
Epithelial Cells
Neoplasms
Autophagy
Standard of Care
Growth
Drug Resistance
Heterografts
Protein-Tyrosine Kinases
Wound Healing
Androgens
Carcinogenesis
Phosphotransferases
Apoptosis
Neoplasm Metastasis
Survival

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor. / Guo, W.; Liu, R.; Bhardwaj, G.; Yang, J. C.; Changou, C.; Ma, A. H.; Mazloom, A.; Chintapalli, S.; Xiao, K.; Xiao, W.; Kumaresan, P.; Sanchez, E.; Yeh, C. T.; Evans, C. P.; Patterson, R.; Lam, K. S.; Kung, H. J.

In: Cell Death and Disease, Vol. 5, No. 9, e1409, 01.01.2014.

Research output: Contribution to journalArticle

Guo, W, Liu, R, Bhardwaj, G, Yang, JC, Changou, C, Ma, AH, Mazloom, A, Chintapalli, S, Xiao, K, Xiao, W, Kumaresan, P, Sanchez, E, Yeh, CT, Evans, CP, Patterson, R, Lam, KS & Kung, HJ 2014, 'Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor', Cell Death and Disease, vol. 5, no. 9, e1409. https://doi.org/10.1038/cddis.2014.343
Guo W, Liu R, Bhardwaj G, Yang JC, Changou C, Ma AH et al. Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor. Cell Death and Disease. 2014 Jan 1;5(9). e1409. https://doi.org/10.1038/cddis.2014.343
Guo, W. ; Liu, R. ; Bhardwaj, G. ; Yang, J. C. ; Changou, C. ; Ma, A. H. ; Mazloom, A. ; Chintapalli, S. ; Xiao, K. ; Xiao, W. ; Kumaresan, P. ; Sanchez, E. ; Yeh, C. T. ; Evans, C. P. ; Patterson, R. ; Lam, K. S. ; Kung, H. J. / Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor. In: Cell Death and Disease. 2014 ; Vol. 5, No. 9.
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abstract = "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.",
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