Article

Nonreceptor tyrosine kinases in prostate cancer.

Department of Urology, University of California at Davis, Sacramento, CA 95817, USA.
Neoplasia (New York, N.Y.) (Impact Factor: 5.4). 03/2007; 9(2):90-100. DOI: 10.1593/neo.06694
Source: PubMed

ABSTRACT Carcinoma of the prostate (CaP) is the most commonly diagnosed cancer in men in the United States. Signal transduction molecules such as tyrosine kinases play important roles in CaP. Src, a nonreceptor tyrosine kinase (NRTK) and the first proto-oncogene discovered is shown to participate in processes such as cell proliferation and migration in CaP. Underscoring NRTK's and, specifically, Src's importance in cancer is the recent approval by the US Food and Drug Administration of dasatinib, the first commercial Src inhibitor for clinical use in chronic myelogenous leukemia (CML). In this review we will focus on NRTKs and their roles in the biology of CaP.
Publicly available literature from PubMed regarding the topic of members of NRTKs in CaP was searched and reviewed.
Src, FAK, JaK1/2, and ETK are involved in processes indispensable to the biology of CaP: cell growth, migration, invasion, angiogenesis, and apoptosis.
Src emerges as a common signaling and regulatory molecule in multiple biological processes in CaP. Src's relative importance in particular stages of CaP, however, required further definition. Continued investigation of NRTKs will increase our understanding of their biological function and potential role as new therapeutic targets.

0 Followers
 · 
67 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer (CaP) recurrence after androgen ablation therapy (ADT) remains a significant cause of mortality in aging men. Malignant progression and metastasis are typically driven by genetic and epigenetic changes controlled by the androgen receptor (AR). However, evidence suggests that activated non-receptor tyrosine kinases, including those of the Src family (SFK), directly phosphorylate AR, thereby activating its transcriptional activity in the absence of serum androgen levels. To ascertain whether CaP progression and metastasis require SFK members an autochthonous transgenic adenocarcinoma (AD) of the mouse prostate (TRAMP) model was crossed into Src-, Lyn- or Fyn-null backgrounds. Primary-site CaP formation was dependent on Src, to a lesser extent, Lyn, but not Fyn. Only Src-/-;TRAMP prostate tumors were marked by reactive stroma. SFK deficiency did not affect progression to neuroendocrine (NE) disease, although there were fewer new cancer cases initiating after 34 weeks in the SFK-/-;TRAMP mice compared to TRAMP controls. Fifteen to 21% of older (>33 weeks) Lyn- or Fyn-null TRAMP mice lacking primary-site tumors suffered from aggressive metastatic AD growths, compared with 3% of TRAMP mice. Taken with the data that TRAMP mice lacking Src or Lyn exhibited fewer macroscopic metastases compared to Fyn-/-;TRAMP and TRAMP controls, this suggests that SFK can either promote or suppress specific parameters of metastatic growth, possibly depending on cross-talk with primary tumors. These data identify critical, yet potentially opposing roles played by various SFKs in the initiation and metastatic potential of CaP using the TRAMP model. Implications: Genetically defined mouse models indicate a critical role for Src tyrosine kinase in prostate cancer initiation and metastatic progression.
    Molecular Cancer Research 07/2014; 12(10). DOI:10.1158/1541-7786.MCR-13-0490-T · 4.50 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Cell Death & Disease 09/2014; 5:e1409. DOI:10.1038/cddis.2014.343 · 5.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A key question for urologic practitioners is whether an apparently organ-confined prostate cancer (PCa) is actually aggressive or not. The dilemma is to specifically identify among all prostate tumors the very aggressive high-grade cancers that will become life-threatening by developing extra-prostatic invasion and metastatic potential and the indolent cancers that will never modify a patient's life expectancy. A choice must be made between several therapeutic options to achieve the optimal personalized management of the disease that causes as little harm as possible to patients. Reliable clinical, biological, or pathological markers that would enable distinctions to be made between aggressive and indolent PCas in routine practice at the time of initial diagnosis are still lacking. The molecular mechanisms that explain why a PCa is aggressive or not are also poorly understood. Among the potential markers and/or actors in PCa aggressiveness, Src and other members of the Src kinase family, are valuable candidates. Activation of Src-dependent intracellular pathways is frequently observed in PCa. Indeed, Src is at the cross-roads of several pathways [including androgen receptor (AR), TGFbeta, Bcl-2, Akt/PTEN or MAPK, and ERK …], and is now known to influence some of the cellular and tissular events that accompany tumor progression: cell proliferation, cell motility, invasion, epithelial-to-mesenchymal transition, resistance to apoptosis, angiogenesis, neuroendocrine differentiation, and metastatic spread. Recent work even suggests that Src could also play a part in PCa initiation in coordination with the AR. The aim of this review is to gather data that explore the links between the Src kinase family and PCa progression and aggressiveness.
    Frontiers in Oncology 08/2014; 4:222. DOI:10.3389/fonc.2014.00222

Full-text (2 Sources)

Download
8 Downloads
Available from
Nov 28, 2014