This competing renewal of a 3-year grant focuses on the role of the protein kinase C (PKC) family of serine-threonine kinases in the control of signaling events that play critical roles in the etiology of prostate cancer, the second leading cause of cancer death in American males. A remarkable feature of androgen-dependent prostate cancer cells is that they undergo apoptosis upon treatment with phorbol esters, the prototypical PKC activators. We have determined that two isozymes, the cPKCalpha and the nPKCdelta, are the mediators of this effect through the modulation of signaling networks that control death and survival. We will perform a comprehensive analysis of the different mechanisms involved in the PKC effect and how they relate to signaling events that are crucial to the etiology of disease. As an extension of the results obtained in the previous period of funding we propose 4 aims.
In Aim 1 we will focus on signaling studies. We will explore the ASK1-MKK3/6-p38 axis as a potential target for PKC in prostate cancer cells. Recent evidence from our laboratory shows that in prostate cancer cells PKC impairs Akt survival signaling, and therefore the contribution of this link will also be studied. This is highly relevant as many prostate tumors and cell lines present mutations in PTEN, a negative regulator of the PI3K/Akt pathway. We will also examine how tyrosine phosphorylation modulates the activity of the pro-apoptotic PKCdelta.
In Aim 2 we will explore the contribution of autocrine mechanisms to the apoptotic effect of PKC isozymes. We present strong evidence that PKC activation in prostate cancer cells triggers the release of autocrine factors with pro-apoptotic activity. We will pursue experiments to identify the factors, receptors and pathways involved in this effect.
In Aim 3 we will study how androgens influence PKC-mediated apoptosis.
This aim i s based on our recent observations that the apoptotic effect mediated by PKC isozymes in LNCaP prostate cancer cells is markedly impaired upon androgen depletion, and that androgens regulate the expression of discrete PKC isozymes. Our hypothesis is that the effect involves the transcriptional control of the PKC genes by androgens and/or post-transcriptional regulatory mechanisms. Lastly, in Aim 4 we will investigate the role of PKC isozymes in prostate tumorigenesis in vivo, both in xenografts in athymic mice as well as in transgenic mice that we have generated for PKC isozymes in the prostate. Our research has the potential to elucidate the complex regulatory mechanisms that control death and survival of prostate cancer cells, and therefore may have important implications from an etiological standpoint as well as the identification of therapeutic targets for this devastating disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Ault, Grace S
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University of Pennsylvania
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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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