Roles of Nemo-like kinase in CaP and its effects on androgen receptor signaling

Summary

Principal Investigator: E Corey
Abstract: The MAPKs regulate cell growth, differentiation, and stress responses, and many critical signaling pathways are subject to cross-regulation by MARK signaling. Previous studies have yielded evidence of crosstalk between the MARK pathways and androgen receptor (AR) signaling, which plays a critical role in growth control of both normal prostate and prostate cancer. We have shown that the MAPK-like protein, Nemo-like kinase (NLK) expression is altered during prostate cancer progression, and that NLK dramatically inhibits AR-mediated signaling and ultimately stimulating apoptosis in CaP cells. The goal of this project is to elucidate the mechanisms of NLK effects on AR signaling in prostate cells and to evaluate its promise as a new therapeutic target. We will perform mechanistic studies on interaction of NLK with AR, including transcriptional analysis and protein-level modifications, and cofactors associations. We will also investigate the proapoptotic effects of NLK in prostate cells and its relation to inhibition of AR signaling, and study in vivo effects of NLK using our advanced animal models. A deeper understanding of the NLK roles in prostate cancer progression and regulation of AR-directed transcription and its biological effects will lead to an appreciation of the value of reconstituting functional NLK signaling in CaP and point the way to new modes of therapeutic intervention in this disease. The specific aims of this proposal are intended to elucidate the nature and mechanisms of induction of apoptosis in CaP cells by NLK and characterize the effects of NLK expression on critical signaling pathways in these cells. Specific aims: 1) To investigate associations of NLK expression with clinical parameters of prostate cancer. 2) To investigate the mechanisms of NLK effects on AR-directed transcription. 3) To investigate the mechanisms whereby NLK promotes apoptosis of CaP cells. 4) To investigate the effects of NLK expression on prostate cancer tumors in vivo. Health relevance: Advanced prostate cancer is a devastating, fatal, and almost untreatable disease. By studying the ability of nemo-like kinase to kill even prostate-cancer cells that are resistant to other treatments, we hope to point the way to new and promising therapeutic approaches for advanced prostate cancer.
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Targeted therapy for advanced prostate cancer: inhibition of the PI3K/Akt/mTOR pathway
    Todd M Morgan
    Department of Urology, University of Washington School of Medicine, Seattle, WA 98195, USA
    Curr Cancer Drug Targets 9:237-49. 2009
  2. pmc Nemo-like kinase induces apoptosis and inhibits androgen receptor signaling in prostate cancer cells
    Katayoon H Emami
    Department of Urology, University of Washington, Seattle, Washington 98195, USA
    Prostate 69:1481-92. 2009
  3. pmc Bone morphogenetic protein 7 is expressed in prostate cancer metastases and its effects on prostate tumor cells depend on cell phenotype and the tumor microenvironment
    Colm Morrissey
    Department of Urology, University of Washington, Seattle, WA 98195, USA
    Neoplasia 12:192-205. 2010

Detail Information

Publications3

  1. pmc Targeted therapy for advanced prostate cancer: inhibition of the PI3K/Akt/mTOR pathway
    Todd M Morgan
    Department of Urology, University of Washington School of Medicine, Seattle, WA 98195, USA
    Curr Cancer Drug Targets 9:237-49. 2009
    ..In this article we review the data surrounding PI3K/Akt/mTOR inhibition in prostate cancer and their clinical implications...
  2. pmc Nemo-like kinase induces apoptosis and inhibits androgen receptor signaling in prostate cancer cells
    Katayoon H Emami
    Department of Urology, University of Washington, Seattle, Washington 98195, USA
    Prostate 69:1481-92. 2009
    ..Objective of this study was to evaluate the expression of MAPK-like protein nemo-like kinase (NLK) in PCa and its effects on AR-mediated transcription...
  3. pmc Bone morphogenetic protein 7 is expressed in prostate cancer metastases and its effects on prostate tumor cells depend on cell phenotype and the tumor microenvironment
    Colm Morrissey
    Department of Urology, University of Washington, Seattle, WA 98195, USA
    Neoplasia 12:192-205. 2010
    ..Further studies are needed to identify changes in BMP-7 signaling that lead to the loss of its control of proliferation during PCa progression...