title: A novel leptin antagonist peptide inhibits breast cancer growth in vitro and in vivo.
abstract: The role of the obesity cytokine leptin in breast cancer progression has raised interest in interfering with leptin's actions as a valuable therapeutic strategy. Leptin interacts with its receptor through three different binding sites: I-III. Site I is crucial for the formation of an active leptin-leptin receptor complex and in its subsequent activation. Amino acids 39-42 (Leu-Asp-Phe-Ile- LDFI) were shown to contribute to leptin binding site I and their mutations in alanine resulted in muteins acting as typical antagonists. We synthesized a small peptide based on the wild-type sequence of leptin binding site I (LDFI) and evaluated its efficacy in antagonizing leptin actions in breast cancer using in vitro and in vivo experimental models. The peptide LDFI abolished the leptin-induced anchorage-dependent and -independent growth as well as the migration of ERα-positive (MCF-7) and -negative (SKBR3) breast cancer cells. These results were well correlated with a reduction in the phosphorylation levels of leptin downstream effectors, as JAK2/STAT3/AKT/MAPK. Importantly, the peptide LDFI reversed the leptin-mediated up-regulation of its gene expression, as an additional mechanism able to enhance the peptide antagonistic activity. The described effects were specific for leptin signalling, since the developed peptide was not able to antagonize the other growth factors' actions on signalling activation, proliferation and migration. Finally, we showed that the LDFI pegylated peptide markedly reduced breast tumour growth in xenograft models. The unmodified peptide LDFI acting as a full leptin antagonist could become an attractive option for breast cancer treatment, especially in obese women.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.forename: Antonella
authors.initials: A
authors.lastname: Leggio
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.forename: Rosaria
authors.initials: R
authors.lastname: De Marco
authors.forename: Luca
authors.initials: L
authors.lastname: Gelsomino
authors.forename: Antonella
authors.initials: A
authors.lastname: Campana
authors.forename: Rocco
authors.initials: R
authors.lastname: Malivindi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panza
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giordano
authors.forename: Alessia
authors.initials: A
authors.lastname: Liguori
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonofiglio
authors.forename: Angelo
authors.initials: A
authors.lastname: Liguori
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015151:Immunoblotting; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011092:Polyethylene Glycols / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020738:Leptin; D009842:Oligopeptides; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D011092:Polyethylene Glycols; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
keywords: breast cancer; leptin; leptin receptor; leptin receptor modulators; peptides