title: The Mechanism by Which MYCN Amplification Confers an Enhanced Sensitivity to a PCNA-Derived Cell Permeable Peptide in Neuroblastoma Cells.
abstract: Dysregulated expression of MYC family genes is a hallmark of many malignancies. Unfortunately, these proteins are not amenable to blockade by small molecules or protein-based therapeutic agents. Therefore, we must find alternative approaches to target MYC-driven cancers. Amplification of MYCN, a MYC family member, predicts high-risk neuroblastoma (NB) disease. We have shown that R9-caPep blocks the interaction of PCNA with its binding partners and selectively kills human NB cells, especially those with MYCN amplification, and we now show the mechanism. We found elevated levels of DNA replication stress in MYCN-amplified NB cells. R9-caPep exacerbated DNA replication stress in MYCN-amplified NB cells and NB cells with an augmented level of MYC by interfering with DNA replication fork extension, leading to Chk1 dependence and susceptibility to Chk1 inhibition. We describe how these effects may be exploited for treating NB.
authors: Department of Molecular & Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States of America.
authors: Long
authors: L
authors: Gu
authors: Department of Pathology, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States of America.
authors: Peiguo
authors: P
authors: Chu
authors: Department of Molecular & Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States of America.
authors: Robert
authors: R
authors: Lingeman
authors: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, United States of America.
authors: Heather
authors: H
authors: McDaniel
authors: Department of Molecular & Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States of America.
authors: Steven
authors: S
authors: Kechichian
authors: Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States of America.
authors: Robert J
authors: RJ
authors: Hickey
authors: Bioinformatic Core, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States of America.
authors: Zheng
authors: Z
authors: Liu
authors: Bioinformatic Core, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States of America.
authors: Yate-Ching
authors: YC
authors: Yuan
authors: Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105, United States of America.
authors: John A
authors: JA
authors: Sandoval
authors: Florida Atlantic University and The Scripps Research Institute/Scripps Florida, Jupiter, FL 33458, United States of America.
authors: Gregg B
authors: GB
authors: Fields
authors: Department of Molecular & Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States of America.
authors: Linda H
authors: LH
authors: Malkas
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000378:metabolism* / Q000494:pharmacology; D000071877:Checkpoint Kinase 1; D004261:DNA Replication / Q000187:drug effects; D004357:Drug Synergism; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D008958:Models, Molecular; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D018809:Proliferating Cell Nuclear Antigen / Q000737:chemistry / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D057846:Cell-Penetrating Peptides; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D018809:Proliferating Cell Nuclear Antigen; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: Chk1; DNA damage response; MYC; MYCN; Neuroblastoma; Proliferating Cell Nuclear Antigen (PCNA); Replication stress