title: Engineering of a disulfide loop instead of a Zn binding loop restores the anti-proliferative, anti-angiogenic and anti-tumor activities of the N-terminal fragment of endostatin: Mechanistic and therapeutic insights.
abstract: Although considerable effort has been devoted to understanding the molecular mechanism of endostatin's anti-cancer activity, the role of its Zn bound N-terminal loop has not been completely clarified. To investigate whether Zn binding or the N-terminal loop is involved in the anti-cancer properties of endostatin, we compared the structure and biological activity of a native Zn binding endostatin peptide (ES-Zn) with three variants: a Zn free variant (ES), a variant containing both a Zn binding site and a disulfide bond (ES-SSZn), and a variant including a disulfide loop but incapable of Zn binding (ES-SS). Spectroscopic studies indicated that ES-Zn and ES-SS consist of random coil and β structures, whereas ES-SSZn and ES fold into random coils. Theoretical analysis proposed that ES-Zn and ES-SS have a similar binding site to αVβ3 integrin. The anti-proliferative activity of endostatin was retained by all peptides except ES, and the in vitro anti-angiogenic property was preserved in ES-Zn and ES-SS. Remarkably, breast tumor growth and CD31 activity were inhibited more effectively by ES-SS than by ES-Zn. Therefore, a correlation exists between the N-terminal loop and anti-cancer properties of endostatin fragment and a disulfide loop may be more promising than a Zn binding loop for inhibiting tumor growth.
authors.affiliation: Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
authors.forename: Reyhane
authors.initials: R
authors.lastname: Chamani
authors.affiliation: Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran. Electronic address: sm_asghari@guilan.ac.ir.
authors.forename: S Mohsen
authors.initials: SM
authors.lastname: Asghari
authors.affiliation: Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ali Mohammad
authors.initials: AM
authors.lastname: Alizadeh
authors.affiliation: Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
authors.forename: Sedigheh
authors.initials: S
authors.lastname: Eskandari
authors.affiliation: Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
authors.forename: Kamran
authors.initials: K
authors.lastname: Mansouri
authors.affiliation: Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Khodarahmi
authors.affiliation: Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Majid
authors.initials: M
authors.lastname: Taghdir
authors.affiliation: Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Heidari
authors.affiliation: Epilepsy Research Center, University of Münster, Münster, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Gorji
authors.affiliation: Department of Chemistry, Faculty of Sciences, University of Guilan, Rasht, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Aliakbar
authors.affiliation: Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Bijan
authors.initials: B
authors.lastname: Ranjbar
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Khosro
authors.initials: K
authors.lastname: Khajeh
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D004220:Disulfides / Q000737:chemistry*; D043169:Endostatins / Q000737:chemistry / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D017433:Protein Structure, Secondary; D015398:Signal Transduction / Q000187:drug effects; D015032:Zinc / Q000737:chemistry*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004220:Disulfides; D043169:Endostatins; D039302:Integrin alphaVbeta3; D010455:Peptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D015032:Zinc
keywords: 5,5′-Dithio-bis-2-nitrobenzoic acid (PubChem CID: 6254); Angiogenesis; Anti-breast tumor activity; Disulfide loop; Endostatin; Ethylenediaminetetraacetic acid (PubChem CID: 6049); Peptide design; Tris hydrochloride (PubChem CID: 93573); Zinc chloride (PubChem CID: 3007855)