The role of PKD3 in prostate carcinogenesis

Summary

Principal Investigator: Qiming Jane Wang
Abstract: This proposal investigates novel signaling mechanisms of protein kinase D (PKD) and its relevance to the pathogenesis of prostate cancer. The family of PKD serine/threonine kinases is a novel target of the key second messenger diacylglycerol (DAG) and its pharmacological analogs, phorbol esters. DAG and phorbol esters directly bind PKD at its C1 domain and activate PKD through phosphorylation via protein kinase C (PKC). Aberrant DAG signaling is closely couples to the etiology of many cancers including the prostate cancer. PKD as a novel DAG target has significant prognostic and therapeutic values for these diseases. Substantial evidence from our studies supports a novel role of PKD3, a new member of the PKD family, in prostate carcinogenesis. We have demonstrated progressive nuclear accumulation of PKD3 as well as elevated expression in human prostate tumors, revealing a potential mechanism whereby PKD contributes to the development of prostate cancer. PKD3 promotes prostate cancer cell growth, survival, and migration/invasion, and knockdown of PKD3 inhibits the growth of prostate tumor xenografts in mice. PKD3 signals downstream of PKC5, an oncogenic protein in prostate cancer, and modulates crucial cell growth/survival regulatory pathways including Akt and EKR1/2 in prostate cancer cells. These findings support the crucial role of a constitutively active PKC5/PKD3 pathway in prostate oncogenesis. The proposed studies will further dissect the signaling mechanisms of PKD3 and define its functional impact in the pathogenesis of prostate cancer. If successful, these studies will reveal the potential value of PKD3 as a novel biomarker and therapeutic target for prostate cancer. Ultimately, new strategies may be designed for targeting PKD3 as therapy for prostate cancer as well as other diseases with deregulated DAG signaling. Three specific aims will be tested in this proposal: Specific Aim 1. Determine the role of PKD3 in the pathogenesis of prostate cancer in vivo. Specific Aim 2. Test the hypothesis that the nuclear accumulation of PKD3 as a consequence of constitutively active PKC5/PKD3 is essential for growth, survival, migration/invasion of prostate cancer cells. Specific Aim 3. Determine relevance of PKD3 in acquired phorbol 12-myristate 13-acetate (PMA) resistance and cell proliferation in prostate cancer cells. PUBLIC HEALTH RELEVANCE: The PKD family, as a novel target of diacylglycerol and an effector of PKC, promotes cell growth and survival. PKD has also been implicated in hyperproliferative disorders and cancer. We hypothesize that PKD3 promotes prostate cancer development via a novel signaling pathway involving PKC5/PKD3-mediated activation of Akt and ERK1/2. This research will define the relevance of PKD3 to the pathogenesis of prostate cancer and identify the signaling mechanisms by which PKD3 promotes tumor development. The ultimate goal of this project is to assess the value of PKD3 as a novel marker and/or therapeutic target for prostate cancer. Fundamental new knowledge will be obtained concerning mechanisms of prostate oncogenesis thereby facilitating future design of novel treatment strategies to limit or prevent this deadly disease.
Funding Period: 2009-05-01 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. ncbi Protein kinase D3 (PKD3) contributes to prostate cancer cell growth and survival through a PKCepsilon/PKD3 pathway downstream of Akt and ERK 1/2
    Jun Chen
    Departments of Pharmacology, and Urology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Cancer Res 68:3844-53. 2008
  2. pmc In vitro cytotoxicity, pharmacokinetics, tissue distribution, and metabolism of small-molecule protein kinase D inhibitors, kb-NB142-70 and kb-NB165-09, in mice bearing human cancer xenografts
    Jianxia Guo
    Molecular Therapeutics and Drug Discovery, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, 5117 Centre Ave, Room G27b, Pittsburgh, PA 15213, USA
    Cancer Chemother Pharmacol 71:331-44. 2013
  3. pmc A targeted library screen reveals a new inhibitor scaffold for protein kinase D
    Manuj Tandon
    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
    PLoS ONE 7:e44653. 2012
  4. pmc PKD2 and PKD3 promote prostate cancer cell invasion by modulating NF-κB- and HDAC1-mediated expression and activation of uPA
    Zhipeng Zou
    Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
    J Cell Sci 125:4800-11. 2012
  5. pmc Inducible silencing of protein kinase D3 inhibits secretion of tumor-promoting factors in prostate cancer
    Courtney R LaValle
    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    Mol Cancer Ther 11:1389-99. 2012
  6. pmc Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity
    Elizabeth R Sharlow
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia, United States of America
    PLoS ONE 6:e25134. 2011
  7. pmc A protein kinase C/protein kinase D pathway protects LNCaP prostate cancer cells from phorbol ester-induced apoptosis by promoting ERK1/2 and NF-{kappa}B activities
    Jun Chen
    Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    Carcinogenesis 32:1198-206. 2011
  8. pmc A role for zinc in regulating hypoxia-induced contractile events in pulmonary endothelium
    Paula J Bernal
    Department of Cell Biology, The University of Pittsburgh, Pennsylvania 15219, USA
    Am J Physiol Lung Cell Mol Physiol 300:L874-86. 2011
  9. pmc Protein kinase D as a potential new target for cancer therapy
    Courtney R LaValle
    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
    Biochim Biophys Acta 1806:183-92. 2010
  10. pmc Novel protein kinase D inhibitors cause potent arrest in prostate cancer cell growth and motility
    Courtney R LaValle
    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    BMC Chem Biol 10:5. 2010

Research Grants

Detail Information

Publications14

  1. ncbi Protein kinase D3 (PKD3) contributes to prostate cancer cell growth and survival through a PKCepsilon/PKD3 pathway downstream of Akt and ERK 1/2
    Jun Chen
    Departments of Pharmacology, and Urology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Cancer Res 68:3844-53. 2008
    ..In summary, our data indicate that PKD3 contributes to growth and survival of prostate cancer cells and may represent a novel therapeutic target for prostate cancer...
  2. pmc In vitro cytotoxicity, pharmacokinetics, tissue distribution, and metabolism of small-molecule protein kinase D inhibitors, kb-NB142-70 and kb-NB165-09, in mice bearing human cancer xenografts
    Jianxia Guo
    Molecular Therapeutics and Drug Discovery, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, 5117 Centre Ave, Room G27b, Pittsburgh, PA 15213, USA
    Cancer Chemother Pharmacol 71:331-44. 2013
    ..Therefore, PKD inhibitors may have therapeutic potential. We evaluated the in vitro cytotoxicity of two PKD inhibitors, kb-NB142-70 and its methoxy analogue, kb-NB165-09, and examined their in vivo efficacy and pharmacokinetics...
  3. pmc A targeted library screen reveals a new inhibitor scaffold for protein kinase D
    Manuj Tandon
    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
    PLoS ONE 7:e44653. 2012
    ..These lead structures represent an excellent starting point for the further optimization and the design of selective and therapeutically effective small molecule inhibitors of PKD...
  4. pmc PKD2 and PKD3 promote prostate cancer cell invasion by modulating NF-κB- and HDAC1-mediated expression and activation of uPA
    Zhipeng Zou
    Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
    J Cell Sci 125:4800-11. 2012
    ..Taken together, these data suggest that PKD2 and PKD3 coordinate to promote prostate cancer cell invasion through p65 NF-κB- and HDAC1-mediated expression and activation of uPA...
  5. pmc Inducible silencing of protein kinase D3 inhibits secretion of tumor-promoting factors in prostate cancer
    Courtney R LaValle
    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    Mol Cancer Ther 11:1389-99. 2012
    ..These data validate PKD3 as a promising therapeutic target in prostate cancer and shed light on the role of secreted tumor-promoting factors in prostate cancer progression...
  6. pmc Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity
    Elizabeth R Sharlow
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia, United States of America
    PLoS ONE 6:e25134. 2011
    ..In summary, we have discovered novel PKD1 inhibitors with in vitro and cell-based inhibitory activity, thus successfully expanding the structural diversity of small molecule inhibitors available for this important pharmacological target...
  7. pmc A protein kinase C/protein kinase D pathway protects LNCaP prostate cancer cells from phorbol ester-induced apoptosis by promoting ERK1/2 and NF-{kappa}B activities
    Jun Chen
    Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    Carcinogenesis 32:1198-206. 2011
    ....
  8. pmc A role for zinc in regulating hypoxia-induced contractile events in pulmonary endothelium
    Paula J Bernal
    Department of Cell Biology, The University of Pittsburgh, Pennsylvania 15219, USA
    Am J Physiol Lung Cell Mol Physiol 300:L874-86. 2011
    ....
  9. pmc Protein kinase D as a potential new target for cancer therapy
    Courtney R LaValle
    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
    Biochim Biophys Acta 1806:183-92. 2010
    ..This review focuses on the potential of PKD as a chemotherapeutic target in cancer treatment and highlights important recent advances in the development of PKD inhibitors...
  10. pmc Novel protein kinase D inhibitors cause potent arrest in prostate cancer cell growth and motility
    Courtney R LaValle
    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    BMC Chem Biol 10:5. 2010
    ..In an effort to further enhance its selectivity and potency for potential in vivo application, small molecule analogs of CID755673 were generated by modifying both the core structure and side-chains...
  11. pmc Potent and selective disruption of protein kinase D functionality by a benzoxoloazepinolone
    Elizabeth R Sharlow
    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    J Biol Chem 283:33516-26. 2008
    ..In summary, our findings indicate that CID755673 is a potent and selective PKD1 inhibitor with valuable pharmacological and cell biological potential...
  12. pmc New pyrazolopyrimidine inhibitors of protein kinase d as potent anticancer agents for prostate cancer cells
    Manuj Tandon
    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
    PLoS ONE 8:e75601. 2013
    ....

Research Grants30

  1. Novel Targets of Indoles in Prostate Cancer
    Fazlul H Sarkar; Fiscal Year: 2013
    ..The results of our study will help to design mechanism-based clinical trials for assessing the role of B-DIM in the prevention and/or treatment of PCa. ..
  2. Development of small molecule inhibitors of protein kinase D
    Qiming Jane Wang; Fiscal Year: 2013
    ..It will also provide the foundation for potential future clinical development of the compounds as novel antitumor agents. ..
  3. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  4. Regulation of Polycomb Repressive Complex 1 by EZH2 Regulated microRNAs in Cancer
    Sooryanarayana Varambally; Fiscal Year: 2013
    ....