title: Novel peptide binds EWS-FLI1 and reduces the oncogenic potential in Ewing tumors.
abstract: Ewing tumor is driven by the oncogenic EWS-FLI1 fusion protein that functions as an aberrant transcription factor. The identification of EWS-FLI1 protein partners is essential to enhance its vulnerability as a therapeutic target. We utilized phage display library screening against recombinant EWS-FLI1 protein. We identified 27 unique Ewing sarcoma binding peptides. The cytotoxicity evaluation of these peptides with in EWS-FLI1 containing cell lines yielded one potent peptide called ESAP1 (TMRGKKKRTRAN). ESAP1 binds EWS-FLI1 with 0.202 micromolar affinity as measured in surface plasmon resonance. The minimal interaction region of ESAP1 is characterized and found that the lysine residues are critical for cellular cytotoxicity. ESAP1 reduces the transcriptional activity of EWS-FLI1 as well as disrupts cell cycle kinetics in Ewing Tumor cells. These findings provide both a novel experimental probe and a potential therapeutic scaffold for Ewing Tumor.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
authors.forename: Hayriye V
authors.initials: HV
authors.lastname: Erkizan
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Scher
authors.forename: S Ellen
authors.initials: SE
authors.lastname: Gamble
authors.forename: Julie S
authors.initials: JS
authors.lastname: Barber-Rotenberg
authors.forename: Kamal P
authors.initials: KP
authors.lastname: Sajwan
authors.forename: Aykut
authors.initials: A
authors.lastname: Üren
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Toretsky
mesh_terms: D000595:Amino Acid Sequence; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D006801:Humans; D007700:Kinetics; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D051789:Proto-Oncogene Protein c-fli-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034802:RNA-Binding Protein EWS / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000473:pathology*; D020349:Surface Plasmon Resonance; D015533:Transcriptional Activation
chemical_list: C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D019151:Peptide Library; D010455:Peptides; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D011993:Recombinant Fusion Proteins