Targeting Neuropeptide Y/DPP4 Signalling Suppresses Ewing Sarcoma Survival and Improves Monocyte Viability

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Metastatic Ewing sarcoma (EwS) has poor survival rates, necessitating novel chemotherapeutic strategies.
• The Neuropeptide Y (NPY) signaling pathway is implicated in EwS cell survival.
• Hypoxia, dipeptidyl peptidase-4 (DPP4/CD26), and immune cell interactions complicate NPY signaling in EwS.

Purpose of the Study:

• To investigate the roles of NPY and DPP4 in EwS cell survival and interactions with monocytes.
• To identify potential therapeutic targets for drug repurposing in EwS treatment.

Main Methods:

• Ewing sarcoma cell lines (A673, SK-ES-1) and THP-1 monocytes were used.
• NPY and DPP4 effects on cell viability, metabolism, and cell death were assessed.
• The NPY1R antagonist BMS-193885 and the DPP4 inhibitor linagliptin were tested.

Main Results:

• Both EwS cell lines secreted NPY; recombinant NPY enhanced EwS viability.
• Recombinant DPP4 promoted EwS viability and metabolism, particularly under hypoxia.
• Linagliptin suppressed EwS viability, with increased efficacy under hypoxic conditions.
• NPY and DPP4 had opposing effects on monocyte viability and metabolism.

Conclusions:

• NPY and DPP4 signaling pathways enhance EwS survival via autocrine/paracrine mechanisms.
• Targeting the NPY/DPP4 axis may suppress EwS growth and improve immunotherapy efficacy.
• Linagliptin shows promise as a therapeutic agent for metastatic Ewing sarcoma, especially in hypoxic environments.