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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 ER?-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.

SUBMITTER: Catalano S

PROVIDER: S-EPMC4420614 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Catalano Stefania S Leggio Antonella A Barone Ines I De Marco Rosaria R Gelsomino Luca L Campana Antonella A Malivindi Rocco R Panza Salvatore S Giordano Cinzia C Liguori Alessia A Bonofiglio Daniela D Liguori Angelo A Andò Sebastiano S

Journal of cellular and molecular medicine 20150227 5

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 ...[more]

PMID: 25721149

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

Publications

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

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