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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089202-15
Application #
8896301
Study Section
Special Emphasis Panel (ZRG1-CE-M (09))
Program Officer
Ault, Grace S
Project Start
2000-12-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
15
Fiscal Year
2015
Total Cost
$325,646
Indirect Cost
$114,071
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Garg, Rachana; Blando, Jorge M; Perez, Carlos J et al. (2018) COX-2 mediates pro-tumorigenic effects of PKC? in prostate cancer. Oncogene 37:4735-4749
Garg, Rachana; Blando, Jorge M; Perez, Carlos J et al. (2017) Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway. Cell Rep 19:375-388
Gutierrez-Uzquiza, Alvaro; Lopez-Haber, Cynthia; Jernigan, Danielle L et al. (2015) PKC? Is an Essential Mediator of Prostate Cancer Bone Metastasis. Mol Cancer Res 13:1336-46
Abera, Mahlet B; Kazanietz, Marcelo G (2015) Protein kinase C? mediates erlotinib resistance in lung cancer cells. Mol Pharmacol 87:832-41
Wang, HongBin; Gutierrez-Uzquiza, Alvaro; Garg, Rachana et al. (2014) Transcriptional regulation of oncogenic protein kinase C? (PKC?) by STAT1 and Sp1 proteins. J Biol Chem 289:19823-38
Garg, R; Benedetti, L G; Abera, M B et al. (2014) Protein kinase C and cancer: what we know and what we do not. Oncogene 33:5225-37
Sviridonov, Ludmila; Dobkin-Bekman, Masha; Shterntal, Boris et al. (2013) Differential signaling of the GnRH receptor in pituitary gonadotrope cell lines and prostate cancer cell lines. Mol Cell Endocrinol 369:107-18
Garg, Rachana; Caino, M Cecilia; Kazanietz, Marcelo G (2013) Regulation of Transcriptional Networks by PKC Isozymes: Identification of c-Rel as a Key Transcription Factor for PKC-Regulated Genes. PLoS One 8:e67319
Garg, Rachana; Blando, Jorge; Perez, Carlos J et al. (2012) Activation of nuclear factor ?B (NF-?B) in prostate cancer is mediated by protein kinase C epsilon (PKCepsilon). J Biol Chem 287:37570-82
Urtreger, Alejandro J; Kazanietz, Marcelo G; Bal de Kier Joffé, Elisa D (2012) Contribution of individual PKC isoforms to breast cancer progression. IUBMB Life 64:18-26

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