C-Myc Phosphorylation By Pkc Zeta Represses Prostate Tumorigenesis

Studies showing reduced PKC zeta expression or enzymatic activity in different types of human cancers support the clinical relevance of PKC zeta as a tumor suppressor. However, the in vivo role of PKC zeta and its mechanisms of action in prostate cancer remain unclear. Here we demonstrate that the genetic inactivation of PKC zeta 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 PKC zeta-inactive cells, which correlated with increased cell growth, invasion, and metastasis. Interestingly, PKC zeta 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 PKC zeta knockout tumors. In vivo xenograft studies revealed that c-Myc phosphorylation by PKC zeta is a critical event in the control of metastasis. Collectively, these results establish PKC zeta as an important tumor suppressor and regulator of c-Myc function in prostate cancer.