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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129127-05
Application #
8444567
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2009-05-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$286,637
Indirect Cost
$97,438
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Guo, Jianxia; Clausen, Dana M; Beumer, Jan H et al. (2013) 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. Cancer Chemother Pharmacol 71:331-44
Bravo-Altamirano, Karla; George, Kara M; Frantz, Marie-Céline et al. (2011) Synthesis and Structure-Activity Relationships of Benzothienothiazepinone Inhibitors of Protein Kinase D. ACS Med Chem Lett 2:154-159
Bernal, Paula J; Bauer, Eileen M; Cao, Rong et al. (2011) A role for zinc in regulating hypoxia-induced contractile events in pulmonary endothelium. Am J Physiol Lung Cell Mol Physiol 300:L874-86
Sharlow, Elizabeth R; Mustata Wilson, Gabriela; Close, David et al. (2011) Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity. PLoS One 6:e25134
George, Kara M; Frantz, Marie-Céline; Bravo-Altamirano, Karla et al. (2011) Design, Synthesis, and Biological Evaluation of PKD Inhibitors. Pharmaceutics 3:186-228
Chen, Jun; Giridhar, Karthik V; Zhang, Liyong et al. (2011) 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. Carcinogenesis 32:1198-206
LaValle, Courtney R; George, Kara M; Sharlow, Elizabeth R et al. (2010) Protein kinase D as a potential new target for cancer therapy. Biochim Biophys Acta 1806:183-92