Journal Article

A novel leptin antagonist peptide inhibits breast cancer growth in vitro and in vivo

Bonofiglio, Daniela, Gelsomino, Luca, Malivindi, Rocco, Andò, Sebastiano, Giordano, Cinzia, Liguori, Angelo, De Marco, Rosaria, Panza, Salvatore, Leggio, Antonella, Liguori, Alessia, Campana, Antonella, Barone, Ines, Catalano, Stefania

2015

Overview

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.

• Publisher: John Wiley & Sons, Inc,BlackWell Publishing Ltd
• Subject: AKT protein / Alanine / Amino Acid Sequence / Amino acids / Antagonists / Binding sites / Breast cancer / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Breast Neoplasms - prevention & control / Cell Line, Tumor / Cell Movement - drug effects / Cell Proliferation - drug effects / Cell Survival - drug effects / Dose-Response Relationship, Drug / Epidermal growth factor / Gene expression / Growth factors / Humans / Immunoblotting / Janus kinase 2 / Kinases / leptin / Leptin - antagonists & inhibitors / Leptin - genetics / Leptin - metabolism / leptin receptor / leptin receptor modulators / MAP kinase / MCF-7 Cells / Mitogen-Activated Protein Kinases - metabolism / Obesity / Oligopeptides - chemistry / Oligopeptides - pharmacology / Original / Peptides / Phosphorylation / Phosphorylation - drug effects / Polyethylene glycol / Polyethylene Glycols - chemistry / Proteins / Proto-Oncogene Proteins c-akt - metabolism / Receptors, Leptin - antagonists & inhibitors / Receptors, Leptin - metabolism / Reverse Transcriptase Polymerase Chain Reaction / Stat3 protein / STAT3 Transcription Factor - metabolism / Tumor Burden - drug effects / Tumors / Xenograft Model Antitumor Assays / Xenografts