Protein kinase C and cancer: what we know and what we do not

Abstract

Since their discovery in the late 1970s, protein kinase C (PKC) isozymes represent one of the most extensively studied signaling kinases. PKCs signal through multiple pathways and control the expression of genes relevant for cell cycle progression, tumorigenesis and metastatic dissemination. Despite the vast amount of information concerning the mechanisms that control PKC activation and function in cellular models, the relevance of individual PKC isozymes in the progression of human cancer is still a matter of controversy. Although the expression of PKC isozymes is altered in multiple cancer types, the causal relationship between such changes and the initiation and progression of the disease remains poorly defined. Animal models developed in the last years helped to better understand the involvement of individual PKCs in various cancer types and in the context of specific oncogenic alterations. Unraveling the enormous complexity in the mechanisms by which PKC isozymes have an impact on tumorigenesis and metastasis is key for reassessing their potential as pharmacological targets for cancer treatment.

Figure 1

Structure of PKC isozymes. PKCs are multidomain proteins that are regulated by lipids and protein-protein interactions. Diacyclycerol (DAG) generated upon activation of receptors causes the activation of cPKCs and nPKCs, and its actions are mimicked by phorbol esters. aPKCs do not respond to DAG or phorbol esters. PKCs activate a number of signal transduction pathways that regulate tumorigenesis and metastasis.

Figure 2

Expression of PKCε in prostate cancer. (a) In silico PKCε mRNA expression profiling in 81 normal/normal adjacent prostate tumors, 48 primary prostate carcinomas and 25 prostate cancer metastasis obtained from a publicly available dataset (GSE6919). PRKCE, PKCε gene. (b) Meta-analysis of PRKCE mRNA expression across 16 prostate microarray studies from the Oncomine database. This meta-analysis shows non-statistically significant differences in PRKCE mRNA expression (combined p-value=0.41) between normal and prostate cancer groups. Red intensity is a representative of the statistical significance in mean difference between normal and protate cancer for each study. (c) Expression of PKCε in “normal” immortalized prostate epithelial RWPE-1 cells vs. prostate cancer cells. This figure was originally published by Garg R, Blando J, Perez CJ, Wang H, Benavides FJ, and Kazanietz MG. in J Biol Chem. 2012 287:37570–37582, © The American Society for Biochemistry and Molecular Biology.

Figure 3

Loss of PKCα gene enhances tumor progression. (a) Deletion of the PKCα gene enhances the formation of tumors in APC^Min/+ mice, and those tumors show a more aggressive phenotype. (b) Deletion of PKCα in K-Ras mutant mice resulted in progression of benign tumors to adenocarcinoma. Tumors exhibit high frequency and grade, and are bigger in size.

Figure 4

Multiple biological functions regulated by PKCδ. Studies in cellular models established important roles for PKCδ in apoptosis and as a negative regulator of cell cycle progression. PKCδ has been also implicated in cancer cell motility and invasiveness. Studies using animal models showed that PKCδ can either act as a tumor suppressor or contribute to tumorigenesis depending on the context.

Figure 5

Phenotype of prostate-specific PKCε transgenic mice. Prostate-specific overexpression of PKCε in mice under the control of the probasin (PB) promoter leads to a preneoplastic phenotype. Representative photomicrographs for H&E, phospho-Akt, phospho-NF-κB and phospho-Stat3 staining in ventral prostates from 12-month old male PB-PKCε mice are shown.

Figure 6

Roles of atypical PKCs in cancer. Most evidence points to PKCζ as a tumor suppressor protein and PKCι as an oncogenic kinase.