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      Targeting Tyrosine Kinases and Autophagy in Prostate Cancer

      research-article
      Hormones & Cancer
      Springer-Verlag
      Androgen receptor, Tyrosine kinase, Prostate Cancer, Autophagy, Src

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          Abstract

          Tyrosine kinases play significant roles in tumor progression and therapy resistance. Inhibitors of tyrosine kinases are on the forefront of targeted therapy. For prostate cancer, tyrosine kinases play an additional role in the development of castration-resistant disease state, the most troubling aspect of prostate cancinogenesis which presently defies any effective treatment. Among the 30 or so tyrosine kinases expressed in a typical prostate cancer cell, nearly one third of them have been implicated in prostate carcinogenesis. Interestingly, most of them channel signals through a trio of non-receptor tyrosine kinases, Src/Etk/FAK, referred here as Src tyrosine kinase complex. This complex has been shown to play a significant role in the aberrant activation of androgen receptor (AR) mediated by growth factors (e.g., epidermal growth factor (EGF)), cytokines (interleukin (IL)-6), chemokines (IL-8), and neurokines (gastrin-releasing peptide). These factors are induced and released from the prostate cancer to the stromal cells upon androgen withdrawal. The Src kinase complex has the ability to phosphorylate androgen receptor, resulting in the nuclear translocation and stabilization of un-liganded androgen receptor. Indeed, tyrosine kinase inhibitors targeting Src can inhibit androgen-independent growth of prostate cancer cells in vitro and in preclinical xenograft model. While effective in inducing growth arrest and inhibiting metastasis of castration-resistant tumors, Src inhibitors rarely induce a significant level of apoptosis. This is also reflected by the general ineffectiveness of tyrosine kinase inhibitors as monotherapy in clinical trials. One of the underlying causes of apoptosis resistance is “autophagy,” which is induced by tyrosine kinase inhibitors and by androgen withdrawal. Autophagy is a self-digesting process to regenerate energy by removal of long-lived proteins and retired organelles to provide a survival mechanism to cells encountering stresses. Excessive autophagy, sometimes, could lead to type II programmed cell death. We demonstrated that autophagy blockade sensitizes prostate cancer cells toward Src tyrosine kinase inhibitor. Thus, a combination therapy based on Src tyrosine kinase inhibitor and autophagy modulator deserves further attention as a potential treatment for relapsed prostate cancer.

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          Most cited references95

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          Integrin-regulated FAK-Src signaling in normal and cancer cells.

          Integrins can alter cellular behavior through the recruitment and activation of signaling proteins such as non-receptor tyrosine kinases including focal adhesion kinase (FAK) and c-Src that form a dual kinase complex. The FAK-Src complex binds to and can phosphorylate various adaptor proteins such as p130Cas and paxillin. In normal cells, multiple integrin-regulated linkages exist to activate FAK or Src. Activated FAK-Src functions to promote cell motility, cell cycle progression and cell survival. Recent studies have found that the FAK-Src complex is activated in many tumor cells and generates signals leading to tumor growth and metastasis. As both FAK and Src catalytic activities are important in promoting VEGF-associated tumor angiogenesis and protease-associated tumor metastasis, support is growing that FAK and Src may be therapeutically relevant targets in the inhibition of tumor progression.
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            Cellular characterization of a novel focal adhesion kinase inhibitor.

            Focal adhesion kinase (FAK) is a member of a family of non-receptor protein-tyrosine kinases that regulates integrin and growth factor signaling pathways involved in cell migration, proliferation, and survival. FAK expression is increased in many cancers, including breast and prostate cancer. Here we describe perturbation of adhesion-mediated signaling with a FAK inhibitor, PF-573,228. In vitro, this compound inhibited purified recombinant catalytic fragment of FAK with an IC(50) of 4 nM. In cultured cells, PF-573,228 inhibited FAK phosphorylation on Tyr(397) with an IC(50) of 30-100 nM. Treatment of cells with concentrations of PF-573,228 that significantly decreased FAK Tyr(397) phosphorylation failed to inhibit cell growth or induce apoptosis. In contrast, treatment with PF-573,228 inhibited both chemotactic and haptotactic migration concomitant with the inhibition of focal adhesion turnover. These studies show that PF-573,228 serves as a useful tool to dissect the functions of FAK in integrin-dependent signaling pathways in normal and cancer cells and forms the basis for the generation of compounds amenable for preclinical and patient trials.
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              Focal adhesion kinase: a regulator of focal adhesion dynamics and cell movement.

              Engagement of integrin receptors with extracellular ligands gives rise to the formation of complex multiprotein structures that link the ECM to the cytoplasmic actin cytoskeleton. These adhesive complexes are dynamic, often heterogeneous structures, varying in size and organization. In motile cells, sites of adhesion within filopodia and lamellipodia are relatively small and transient and are referred to as 'focal complexes,' whereas adhesions underlying the body of the cell and localized to the ends of actin stress fibers are referred to as 'focal adhesions'. Signal transduction through focal complexes and focal adhesions has been implicated in the regulation of a number of key cellular processes, including growth factor induced mitogenic signals, cell survival and cell locomotion. The formation and remodeling of focal contacts is a dynamic process under the regulation of protein tyrosine kinases and small GTPases of the Rho family. In this review, we consider the role of the focal complex associated protein tyrosine kinase, Focal Adhesion Kinase (FAK), in the regulation of cell movement with the emphasis on how FAK regulates the flow of signals from the ECM to the actin cytoskeleton.
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                Author and article information

                Contributors
                hkung@ucdavis.edu
                Journal
                Horm Cancer
                Hormones & Cancer
                Springer-Verlag (New York )
                1868-8497
                1868-8500
                2 December 2010
                2 December 2010
                February 2011
                : 2
                : 1
                : 38-46
                Affiliations
                UC Davis Cancer Center, UCDMC, Res III, Rm. 2400, 4645 2nd Avenue, Sacramento, CA 95817 USA
                Article
                53
                10.1007/s12672-010-0053-3
                3020299
                21350583
                f1f5dea8-ee1d-455d-a204-b7191bdcd099
                © The Author(s) 2010
                History
                Categories
                Article
                Custom metadata
                © Springer Science+Business Media, LLC 2011

                Oncology & Radiotherapy
                src,tyrosine kinase,autophagy,prostate cancer,androgen receptor
                Oncology & Radiotherapy
                src, tyrosine kinase, autophagy, prostate cancer, androgen receptor

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