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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Available from: Michael Leitges, Jan 29, 2016
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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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