title: Origin of anti-tumor activity of the cysteine-containing GO peptides and further optimization of their cytotoxic properties.
abstract: Antitumor GO peptides have been designed as dimerization inhibitors of prominent oncoprotein mucin 1. In this study we demonstrate that activity of GO peptides is independent of the level of cellular expression of mucin 1. Furthermore, these peptides prove to be broadly cytotoxic, causing cell death also in normal cells such as dermal fibroblasts and endometrial mesenchymal stem cells. To explore molecular mechanism of their cytotoxicity, we have designed and tested a number of new peptide sequences containing the key CxC or CxxC motifs. Of note, these sequences bear no similarity to mucin 1 except that they also contain a pair of proximal cysteines. Several of the new peptides turned out to be significantly more potent than their GO prototypes. The results suggest that cytotoxicity of these peptides stems from their (moderate) activity as disulfide oxidoreductases. It is expected that such peptides, which we have termed DO peptides, are involved in disulfide-dithiol exchange reaction, resulting in formation of adventitious disulfide bridges in cell proteins. In turn, this leads to a partial loss of protein function and rapid onset of apoptosis. We anticipate that coupling DO sequences with tumor-homing transduction domains can create a potentially valuable new class of tumoricidal peptides.
authors.affiliation: Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia.|Laboratory of Biomolecular NMR, St. Petersburg State University, St. Petersburg 199034, Russia.
authors.forename: Irina I
authors.initials: II
authors.lastname: Tyuryaeva
authors.affiliation: Department of Intracellular Signaling and Transport, Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia.
authors.forename: Olga G
authors.initials: OG
authors.lastname: Lyublinskaya
authors.affiliation: Laboratory of Biomolecular NMR, St. Petersburg State University, St. Petersburg 199034, Russia.
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Podkorytov
authors.affiliation: Laboratory of Biomolecular NMR, St. Petersburg State University, St. Petersburg 199034, Russia.|Department of Chemistry, Purdue University, West Lafayette IN 47907, USA.
authors.forename: Nikolai R
authors.initials: NR
authors.lastname: Skrynnikov
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004220:Disulfides / Q000378:metabolism; D006801:Humans; D018396:Mucin-1 / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D010084:Oxidation-Reduction
chemical_list: D000970:Antineoplastic Agents; D004220:Disulfides; D018396:Mucin-1; D009842:Oligopeptides