title: A novel non-phosphorylated potential antitumoral peptide inhibits STAT3 biological activity.
abstract: STAT3 (Signal Transducer and Activator of Transcription 3) is an SH2 (Src Homology 2)-domain containing transcription factor that plays a key role in cancer, by regulating as a dimer the expression of genes implicated in the main processes of the tumorigenesis. Therefore, STAT3 and more particularly its dimeric form has emerged as promising targets for cancer therapy. STAT3 dimerization occurs through reciprocal interaction between the SH2 domain of one monomer and the phosphorylated tyrosine residue of a second one. One strategy to design small inhibitors of STAT3 dimerization, consists in using phosphotyrosine-based peptidomimetics targeted to the SH2 domain. We have tested whether a high affinity phosphotyrosyl peptide ligand P1 (AYRNRY( *)RRQYRY) (K(d) = 0.34 microM), issued from combinatorial chemistry, could inhibit STAT3 dimerization and biological activity. This ligand was found to disrupt dimerization with an IC(50) of 9 microM. Further biological evaluation using a STAT3-dependent cell line demonstrated that its Antennapedia-vectorized form P1a interacted with STAT3 within the cell, resulting in a significant effect on cell proliferation and expression of cell cycle and apoptosis regulators controlled by STAT3. More importantly, these studies identified unexpectedly a non-phosphorylated vectorized peptide P2a, as another potent inhibitor of STAT3 biological activity and thus give further insight for the development of novel inhibitors.
authors.affiliation: Université Paris Descartes, UFR Biomédicale, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dourlat
authors.forename: Wang-Qing
authors.initials: WQ
authors.lastname: Liu
authors.forename: Florence
authors.initials: F
authors.lastname: Sancier
authors.forename: Thomas
authors.initials: T
authors.lastname: Edmonds
authors.forename: Perayot
authors.initials: P
authors.lastname: Pamonsinlapatham
authors.forename: Francisco
authors.initials: F
authors.lastname: Cruzalegui
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010748:Phosphopeptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D021381:Protein Transport / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D000970:Antineoplastic Agents; D010748:Phosphopeptides; D050796:STAT3 Transcription Factor; D004247:DNA