title: Inhibition of heat shock protein 27 (HspB1) tumorigenic functions by peptide aptamers.
abstract: Human heat shock protein 27 (Hsp27, HspB1) is an anti-apoptotic protein characterized for its tumorigenic and metastatic properties, and now referenced as a major therapeutic target in many types of cancer. Hsp27 biochemical properties rely on a structural oligomeric and dynamic organization. Downregulation by small interfering RNA or inhibition with dominant-negative mutant have proven their efficiency to counteract the anti-apoptotic and protective properties of Hsp27. In this study, we report the isolation and characterization of Hsp27-targeted molecules interfering with its structural organization. Using the peptide aptamer (PA) strategy, we isolated PAs that specifically interact with Hsp27 and not with the other members of the small heat shock protein family. In mammalian cell cultures, PAs expression perturbed the dimerization and oligomerization of Hsp27, and acted as negative regulators of the anti-apoptotic and cytoprotective activities of this protein. Further studies analyzing SQ20B cell xenografts in immunocompromised mice showed that PAs strongly reduced tumor development through cell cycle arrest. Our data suggest that PAs could provide a potential tool to develop strategies for the discovery of Hsp27 chemical inhibitors.
authors.affiliation: Centre de Génétique Moléculaire et Cellulaire, CNRS UMR5534, Université Lyon 1, Université de Lyon, Lyon, France.
authors.forename: B
authors.initials: B
authors.lastname: Gibert
authors.forename: E
authors.initials: E
authors.lastname: Hadchity
authors.forename: A
authors.initials: A
authors.lastname: Czekalla
authors.forename: M-T
authors.initials: MT
authors.lastname: Aloy
authors.forename: P
authors.initials: P
authors.lastname: Colas
authors.forename: C
authors.initials: C
authors.lastname: Rodriguez-Lafrasse
authors.forename: A-P
authors.initials: AP
authors.lastname: Arrigo
authors.forename: C
authors.initials: C
authors.lastname: Diaz-Latoud
mesh_terms: D000595:Amino Acid Sequence; D052158:Aptamers, Peptide; D001483:Base Sequence; D017931:DNA Primers; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006367:HeLa Cells; D006360:Heat-Shock Proteins; D006801:Humans; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D010957:Plasmids
chemical_list: D052158:Aptamers, Peptide; D017931:DNA Primers; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones