title: Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor.
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.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: W
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: R
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: G
authors.initials: G
authors.lastname: Bhardwaj
authors.affiliation: Department of Urology, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: C
authors.initials: C
authors.lastname: Changou
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: A-H
authors.initials: AH
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mazloom
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA [2] Department of Physiology and Membrane Biology, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chintapalli
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: K
authors.initials: K
authors.lastname: Xiao
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: W
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kumaresan
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: E
authors.initials: E
authors.lastname: Sanchez
authors.affiliation: Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan, ROC.
authors.forename: C-T
authors.initials: CT
authors.lastname: Yeh
authors.affiliation: Department of Urology, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Evans
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA [2] Department of Physiology and Membrane Biology, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: R
authors.initials: R
authors.lastname: Patterson
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Lam
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA 95817, USA [2] Institute of Molecular and Genomic Medicine, National Health Research Institutes (NHRI), Miaoli County 35053, Taiwan, ROC.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Kung
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D001343:Autophagy / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000077143:Docetaxel; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011810:Quinoxalines / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D043823:Taxoids / Q000627:therapeutic use / Q000633:toxicity; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; C000601039:N-(7-isobutyl-6-oxo-1-(3-(piperidin-1-yl)propyl)-5,6-dihydro-1H-imidazo(4,5-g)quinoxalin-2-yl)-4-(pyridin-4-yl)benzamide; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D043823:Taxoids; D000077143:Docetaxel; C492367:BMX protein, human; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D051057:Proto-Oncogene Proteins c-akt; D051966:Phospholipase C gamma