The genesis and progression of prostate cancer involves a series of both genetic and epigenetic changes that result in deregulation of proliferation and survival signals. One notable alteration in human prostate cancer (as well as in several other epithelial cancers) is the marked overexpression of PKCe, a survival and mitogenic Ser-Thr kinase that is a receptor for the phorbol ester tumor promoters. To date it is not known whether PKCe is implicated in the etiology of prostate cancer. The question that remains to be addressed is whether there is a causal relationship between PKCe overexpression and prostate cancer initiation and progression. We generated mouse models to target PKC isozymes to the prostate epithelium using a probasin (PB) promoter. Interestingly, PB-PKCe transgenic mice developed prostatic hyperplasia and intraepithelial neoplastic (PIN) lesions, whereas no obvious phenotype was observed in similar models that we developed for PKCa or PKCd overexpression. Remarkably, when we crossed PB- PKCe mice with heterozygous Pten mice (which also develop preneoplastic lesions), the resulting compound PB-PKCe Pten mice developed invasive prostatic adenocarcinoma. Prostate lesions present elevated levels of active Akt, mTOR, S6, Stat3, and NF-kB. Thus, PKCe overexpression is a potential causative factor for prostate cancer development and cooperates with defined oncogenic alterations.
In Specific Aim 1 the goal is to determine whether PKCe contributes to prostate cancer cell tumorigenicity and dissemination, using both PKCe-deficient prostate cancer cells and a specific PKCe inhibitor (eV1-2).
In Specific Aim 2 we propose to study the mutual requirement for PKCe and the PI3K/Akt axis in prostate tumorigenesis. We will generate prostate-specific PKCe overexpressing/Akt-null mouse models to determine whether Akt is implicated in the formation of prostate lesions driven by PB-PKCe overexpression. We will also test the hypothesis that genetic or pharmacological targeting of PKCe can reverse the malignant phenotype induced by Pten deficiency in mice.
In Specific Aim 3 we will address a potential involvement of NF-kB in PKCe signaling in prostate cancer. NF-kB hyperactivation is a hallmark of prostate cancer, and preliminary data presented in this application show a clear functional relationship between PKCe and NF-kB pathways. Specifically, in this aim we will a) examine if overexpression of PKCe is sufficient to promote NF-kB activation in normal prostate epithelial cells and cooperates with Pten loss to activate NF-kB, b) determine if PKCe is implicated in the constitutive activation of NF-kB observed in prostate cancer, c) characterize the involvement of PKCe in the control of NF-kB-regulated genes, and d) dissect of the mechanisms by which PKCe controls NF-kB activation. Our studies will therefore establish the potential role of PKCe in the etiology of prostate cancer and determine its potential significance as a therapeutic target.

Public Health Relevance

In this application we will characterize a member of the family of phorbol ester receptors, protein kinase C epsilon (PKCe), and its involvement in prostate carcinogenesis. We have established in previous funding periods that phorbol esters, natural compounds that have been instrumental for defining the promotion stage in mutagen-initiated multistage carcinogenesis, regulate prostate cancer cell fate. Discrete members of the PKC family can exert dissimilar responses upon activation with phorbol esters. A main goal in this proposal is to determine whether PKCe is implicated in the etiology of prostate cancer. We will investigate how this phorbol ester receptor interacts with defined genetic alterations in prostate cancer and dissect the mechanistic basis of these interactions both in cellular and animal models. Our studies have the potential to establish a major role for PKCe, a pro-tumorigenic receptor for the phorbol esters, in prostate cancer etiology, and may potentially reveal a novel target for therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Ault, Grace S
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University of Pennsylvania
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