title: A PCNA-derived cell permeable peptide selectively inhibits neuroblastoma cell growth.
abstract: Proliferating cell nuclear antigen (PCNA), through its interaction with various proteins involved in DNA synthesis, cell cycle regulation, and DNA repair, plays a central role in maintaining genome stability. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was significantly expressed in a broad range of cancer cells and tumor tissues, but not in non-malignant cells. We found that the caPCNA-specific antigenic site lies between L126 and Y133, a region within the interconnector domain of PCNA that is known to be a major binding site for many of PCNA's interacting proteins. We hypothesized that therapeutic agents targeting protein-protein interactions mediated through this region may confer differential toxicity to normal and malignant cells. To test this hypothesis, we designed a cell permeable peptide containing the PCNA L126-Y133 sequence. Here, we report that this peptide selectively kills human neuroblastoma cells, especially those with MYCN gene amplification, with much less toxicity to non-malignant human cells. Mechanistically, the peptide is able to block PCNA interactions in cancer cells. It interferes with DNA synthesis and homologous recombination-mediated double-stranded DNA break repair, resulting in S-phase arrest, accumulation of DNA damage, and enhanced sensitivity to cisplatin. These results demonstrate conceptually the utility of this peptide for treating neuroblastomas, particularly, the unfavorable MYCN-amplified tumors.
authors.affiliation: Department of Molecular & Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California, United States of America.
authors.forename: Long
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Molecular & Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California, United States of America.
authors.forename: Shanna
authors.initials: S
authors.lastname: Smith
authors.affiliation: Department of Molecular & Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California, United States of America.
authors.forename: Caroline
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute of City of Hope, Duarte, California, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hickey
authors.affiliation: Department of Radiation Biology, Beckman Research Institute of City of Hope, Duarte, California, United States of America.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Stark
authors.affiliation: Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida, United States of America.
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Fields
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Walter H
authors.initials: WH
authors.lastname: Lang
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: John A
authors.initials: JA
authors.lastname: Sandoval
authors.affiliation: Department of Molecular & Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California, United States of America.
authors.forename: Linda H
authors.initials: LH
authors.lastname: Malkas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D010446:Peptide Fragments; D018809:Proliferating Cell Nuclear Antigen
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