title: Targeting tyrosine phosphorylation of PCNA inhibits prostate cancer growth.
abstract: The proliferation cell nuclear antigen (PCNA) is a critical protein required for DNA replication in proliferating cells including cancer cells. However, direct inhibition of PCNA in cancer cells has been difficult due to the lack of targetable sites. We previously reported that phosphorylation of tyrosine 211 (Y211) on PCNA is important for the proliferative function of PCNA when this protein is associated with the chromatin in cancer cells. Here, we show that the Y211 phosphorylation of PCNA is a frequent event in advanced prostate cancer. To explore the potential of this signaling event in inhibition of cancer cell growth, we used a synthetic peptide, the Y211F peptide, which when present inhibits phosphorylation of Y211 on endogenous PCNA. Treatment with this peptide, but not a scrambled control peptide, resulted in S-phase arrest, inhibition of DNA synthesis, and enhanced cell death in a panel of human prostate cancer cell lines. In addition, treatment with the Y211F peptide led to decreased tumor growth in PC3-derived xenograft tumors in vivo in nude mice. Our study shows for the first time that PCNA phosphorylation at Y211 is a frequent and biologically important signaling event in prostate cancer. This study also shows a proof of concept that Y211 phosphorylation of PCNA may be used as a therapeutic target in prostate cancer cells, including cells of advanced cancers that are refractory to standard hormonal therapies.
authors.affiliation: Corresponding Author: Shao-Chun Wang, Department of Cancer and Cell Biology, 3125 Eden Ave., Cincinnati, OH 45267, USA.
authors.forename: Huajun
authors.initials: H
authors.lastname: Zhao
authors.forename: Yuan-Hung
authors.initials: YH
authors.lastname: Lo
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Susan E
authors.initials: SE
authors.lastname: Waltz
authors.forename: Jerilyn K
authors.initials: JK
authors.lastname: Gray
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Shao-Chun
authors.initials: SC
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D010455:Peptides; D018809:Proliferating Cell Nuclear Antigen; D014443:Tyrosine