C-Myc phosphorylation by PKCζ represses prostate tumorigenesis

Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2013; 110(16). DOI: 10.1073/pnas.1221799110
Source: PubMed


Studies showing reduced PKCζ expression or enzymatic activity in different types of human cancers support the clinical relevance of PKCζ as a tumor suppressor. However, the in vivo role of PKCζ and its mechanisms of action in prostate cancer remain unclear. Here we demonstrate that the genetic inactivation of PKCζ in mice results in invasive prostate carcinoma in vivo in the context of phosphatase and tensin homolog deficiency. Bioinformatic analysis of human prostate cancer gene-expression sets revealed increased c-Myc transcriptional activity in PKCζ-inactive cells, which correlated with increased cell growth, invasion, and metastasis. Interestingly, PKCζ knockdown or the overexpression of a kinase-inactive mutant resulted in enhanced cell proliferation and invasion in vitro through increased c-Myc mRNA and protein levels and decreased Ser-373 phosphorylation of c-Myc. Analysis of prostate cancer samples demonstrated increased expression and decreased phosphorylation of c-Myc at Ser-373 in PKCζ knockout tumors. In vivo xenograft studies revealed that c-Myc phosphorylation by PKCζ is a critical event in the control of metastasis. Collectively, these results establish PKCζ as an important tumor suppressor and regulator of c-Myc function in prostate cancer.

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    • "Expression of other, less characterized isoforms of aPKC has also been reported in prostate cancer [12]. Notwithstanding, aPKCξ has also been described as a tumor suppressor in prostate cancer [13] and therefore the association of this kinase with prostate cancer remains controversial. Therefore, we sought to investigate if the reported increase in expression of aPKC isoforms in prostate cancer extends to a Japanese cohort or is subject to ethnic variations. "
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    ABSTRACT: . Levels of the protein kinase aPKC have been previously correlated with prostate cancer prognosis in a British cohort. However, prostate cancer incidence and progression rates, as well as genetic changes in this disease, show strong ethnic variance, particularly in Asian populations. Objective . The aim of this study was to validate association of aPKC expression with prostatic adenocarcinoma stages in a Japanese cohort. Methods . Tissue microarrays consisting of 142 malignant prostate cancer cases and 21 benign prostate tissues were subject to immunohistological staining for aPKC. aPKC staining intensity was scored by three independent pathologists and categorized as absent (0), dim (1+), intermediate (2+), and bright (3+). aPKC staining intensities were correlated with Gleason score and tumor stage. Results . Increased aPKC staining was observed in malignant prostate cancer, in comparison to benign tissue. Additionally, aPKC staining levels correlated with Gleason score and tumor stage. Our results extend the association of aPKC with prostate cancer to a Japanese population and establish the suitability of aPKC as a universal prostate cancer biomarker that performs consistently across ethnicities.
    04/2014; 2014(1):481697. DOI:10.1155/2014/481697
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    ABSTRACT: Atypical protein kinase C isoforms are serine threonine kinases involved in various pathological conditions. In recent years, the PKCζ isoform has emerged as an important regulator of multiple cellular processes operating in cancer. In this review, we will focus on the PKCζ isoform as an oxidative-sensing kinase involved in cancer-related inflammation and chemoresistance. We will discuss its nuclear localization and its possible pivotal role in connecting inflammation with drug resistance.
    Frontiers in Oncology 09/2013; 3:232. DOI:10.3389/fonc.2013.00232
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    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.Oncogene advance online publication, 16 December 2013; doi:10.1038/onc.2013.524.
    Oncogene 12/2013; 33(45). DOI:10.1038/onc.2013.524 · 8.46 Impact Factor
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