title: c-Myc phosphorylation by PKCζ represses prostate tumorigenesis.
abstract: 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.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Tania
authors.initials: T
authors.lastname: Valencia
authors.forename: Shadi
authors.initials: S
authors.lastname: Abu-Baker
authors.forename: Juan
authors.initials: J
authors.lastname: Linares
authors.forename: Sang Jun
authors.initials: SJ
authors.lastname: Lee
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yajima
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Alexey
authors.initials: A
authors.lastname: Eroshkin
authors.forename: Elias A
authors.initials: EA
authors.lastname: Castilla
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Brill
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019295:Computational Biology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D008156:Luciferases; D008297:Male; D051379:Mice; D046228:Microarray Analysis; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000099221:Protein Kinase C zeta
chemical_list: D008156:Luciferases; D051059:PTEN Phosphohydrolase; D011493:Protein Kinase C; D016271:Proto-Oncogene Proteins c-myc; D000099221:Protein Kinase C zeta; C489428:Myc protein, mouse; C487757:Pten protein, mouse
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