Prostate carcinogenesis and PKC signaling

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DESCRIPTION (provided by applicant): The phorbol esters are natural compounds with tumor promoter activity that have been instrumental to define the stages of mutagen-initiated multistage carcinogenesis. Phorbol esters act primarily through the activation of protein kinase C (PKC), a family of serine-threonine kinases that modulate pathways involved in cell growth and malignant transformation. Paradoxically, despite their well-established tumor promoter activity, phorbol esters can cause growth inhibition or apoptosis in many cell types, suggesting diverse functional roles for individual PKC isozymes. In previous funding periods we established that phorbol esters cause apoptosis in prostate cancer cells via PKC?-induced activation of the extrinsic apoptotic cascade, p38 and JNK cascades. On the other hand, PKC? confers survival to prostate cancer cells against a number of death stimuli, including phorbol esters, cytokines, and radiation, and it mediates prostate cancer cell motility, thus highlighting the dissimilar biological roles of individual PKC isozymes. These results are also highly relevant because PKC? is markedly up-regulated in human prostate cancer, particularly in high-grade tumors. Not surprisingly, studies have implicated PKC? overexpression in the etiology of other cancers such as breast and lung cancer. To address the relevance of our findings we generated prostate-specific transgenic mice under the control of a probasin (PB) promoter. While no obvious phenotype was observed in PB-PKC? or PB-PKC? mice, PB-PKC??mice develop prostatic hyperplasia and intraepithelial neoplastic (PIN) lesions. As Pten deficiency is a common oncogenic alteration in prostate cancer, we crossed PB-PKC? mice with heterozygous Pten mice, which also develop preneoplastic lesions. Remarkably, PB-PKC?;Pten mice developed invasive prostatic adenocarcinoma with very high phospho-Akt levels. Thus, PKC? overexpression confers survival signaling and possibly contributes to the etiology of prostate cancer by cooperating with other oncogenic injuries. In Specific Aim 1 the goal is to determine whether PKC? contributes to prostate cancer cell tumorigenicity and dissemination, using both PKC?-deficient prostate cancer cells and a specific PKC? inhibitor (5V1-2). In Specific Aim 2 we will pursue a molecular characterization of the lesions driven by PKC? overexpression. We speculate that PINs and adenocarcinomas from PKC? overexpressing prostates have major dysregulations in mitogenic and/or survival pathways, and wish to determine the molecular signals driving the phenotypes, including Akt and its effectors. We will also test the hypothesis that PKC? overexpression leads to genomic instability and biallelic loss of Pten. In Specific Aim 3 we propose to generate a prostate-specific PKC? overexpressing/Akt-null mouse model to determine whether Akt is implicated in the formation of prostate lesions in PB-PKC? mice. We will also test the hypothesis that genetic or pharmacological targeting of PKC5 can reverse the malignant phenotype induced by Pten deficiency in mice. Our studies have the potential to establish a major role for PKC?, a pro-tumorigenic receptor for the phorbol esters, in prostate cancer etiology. PUBLIC HEALTH RELEVANCE: In this application we will characterize a member of the family of phorbol ester receptors, protein kinase C epsilon (PKC?), and its involvement in prostate carcinogenesis. In the previous funding period we have established that phorbol esters, natural compounds that have been instrumental for defining the promotion stage in mutagen-initiated multistage carcinogenesis, exert major effects on prostate cancer cells related to cell fate. We have established that individual members of the PKC family can exert dissimilar responses upon activation with phorbol esters. As PKC isozymes have been implicated in the etiology of several types of cancers, including prostate cancer, we wish to determine the contribution of PKC? to prostate carcinogenesis. We will investigate how this phorbol ester receptor interacts with defined alterations in prostate cancer and the mechanistic basis of these effects using cellular and animal models. Our studies have the potential to establish a major role for PKC?, a pro-tumorigenic receptor for the phorbol esters, in prostate cancer etiology, and may potentially reveal a novel target for therapy.