Nonreceptor tyrosine kinases in prostate cancer

Abstract

Background: 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.

Materials and methods: Publicly available literature from PubMed regarding the topic of members of NRTKs in CaP was searched and reviewed.

Results: Src, FAK, JaK1/2, and ETK are involved in processes indispensable to the biology of CaP: cell growth, migration, invasion, angiogenesis, and apoptosis.

Conclusions: 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.

Figure 1

NRTK families and their members in a guide tree. Protein sequences are obtained from Entrez Gene and aligned using Vector NTI Advance software (Invitrogen, Carlsbad, CA). Vector NTI Advance uses the neighbor-joining method of phylogenetic tree construction by Saitou and Nei [127]. The numbers in parentheses after each kinase reflect the calculated distance values between pairs of analyzed sequences.

Figure 2

Summary of NRTK mRNA or protein expression in CWR22Rv1, DU145, LNCaP, and PC3 cell lines based on internal data and published reports. NRTK domain drawings and domain information were derived from Simple Modular Architecture Research Tool (SMART, Heidelberg, Germany).

Figure 3

Western blot analysis of total Src protein expression levels in prostate cancer cell lines. Src is shown as a doublet upon probing in most cell lines. Internal overexpression data (not shown) indicate that both bands are Src and that the doublet is not a result of nonspecific probing of other Src family kinase members.

Figure 4

Known Src pathways in prostate cancer. The close proximity of molecules not connected with arrows denote physical association. Red arrows denote activation. Black arrows denote change in levels of molecule. Figure templates were provided by BioCarta (San Diego, CA).