Neuropeptide Y in cancer metastasis and chemoresistance

Neuropeptide Y (NPY) is a sympathetic neurotransmitter, abundant in the central and peripheral nervous systems. Acting via its G protein-coupled receptors, Y1R, Y2R and Y5R, NPY regulates many physiological processes, such as stress response, the immune system, and metabolism. NPY and its receptors are also expressed in a variety of malignancies, including rare pediatric tumors, neuroblastoma and Ewing sarcoma, as well as common adulthood cancers of the breast, prostate, liver, and pancreas. While the majority of early studies focused on the role of the NPY system in the regulation of cancer cell proliferation and tumor growth, recent evidence indicates its contribution to cancer metastasis and therapy resistance. NPY acting in the cancer-type- and receptor-specific manner stimulates motility and invasiveness via extracellular signal-regulated kinase 1/2 (ERK1/2) and RhoA pathways, while its interactions with nuclear transcription factor-κB (NF-κB) and brain-derived neurotrophic factor (BDNF) enhance resistance to chemo- and radiotherapy. These effects are exerted by autocrine NPY secreted from tumor cells, as shown in neuroblastoma and Ewing sarcoma, and by the peptide present in the tumor microenvironment, e.g., released from nerves. In addition to direct effects on cancer cells, NPY can modify the environment in the primary tumor or in the metastatic niche. Consequently, the direct in vivo evidence for the role of NPY in metastasis and clinical data associating the expression of NPY and its receptor with adverse disease phenotypes are growing. Understanding the mechanisms underlying these effects may lead to the design of novel therapeutic approaches targeting the NPY system to prevent cancer progression.