title: Hypoxia shifts activity of neuropeptide Y in Ewing sarcoma from growth-inhibitory to growth-promoting effects.
abstract: Ewing sarcoma (ES) is an aggressive malignancy driven by an oncogenic fusion protein, EWS-FLI1. Neuropeptide Y (NPY), and two of its receptors, Y1R and Y5R are up-regulated by EWS-FLI1 and abundantly expressed in ES cells. Paradoxically, NPY acting via Y1R and Y5R stimulates ES cell death. Here, we demonstrate that these growth-inhibitory actions of NPY are counteracted by hypoxia, which converts the peptide to a growth-promoting factor. In ES cells, hypoxia induces another NPY receptor, Y2R, and increases expression of dipeptidyl peptidase IV (DPPIV), an enzyme that cleaves NPY to a shorter form, NPY3-36. This truncated peptide no longer binds to Y1R and, therefore, does not stimulate ES cell death. Instead, NPY3-36 acts as a selective Y2R/Y5R agonist. The hypoxia-induced increase in DPPIV activity is most evident in a population of ES cells with high aldehyde dehydrogenase (ALDH) activity, rich in cancer stem cells (CSCs). Consequently, NPY, acting via Y2R/Y5Rs, preferentially stimulates proliferation and migration of hypoxic ALDHhigh cells. Hypoxia also enhances the angiogenic potential of ES by inducing Y2Rs in endothelial cells and increasing the release of its ligand, NPY3-36, from ES cells. In summary, hypoxia acts as a molecular switch shifting NPY activity away from Y1R/Y5R-mediated cell death and activating the Y2R/Y5R/DPPIV/NPY3-36 axis, which stimulates ES CSCs and promotes angiogenesis. Hypoxia-driven actions of the peptide such as these may contribute to ES progression. Due to the receptor-specific and multifaceted nature of NPY actions, these findings may inform novel therapeutic approaches to ES.
authors: Department of Nursing, Georgetown University Medical Center, Georgetown University, Washington DC.
authors: Jason U
authors: JU
authors: Tilan
authors: Congyi
authors: C
authors: Lu
authors: Susana
authors: S
authors: Galli
authors: Ewa
authors: E
authors: Izycka-Swieszewska
authors: Joshua Patrick
authors: JP
authors: Earnest
authors: Asim
authors: A
authors: Shabbir
authors: Lindsay M
authors: LM
authors: Everhart
authors: Shuo
authors: S
authors: Wang
authors: Samantha
authors: S
authors: Martin
authors: Meredith
authors: M
authors: Horton
authors: Akanksha
authors: A
authors: Mahajan
authors: David
authors: D
authors: Christian
authors: Alison
authors: A
authors: O'Neill
authors: Hongkun
authors: H
authors: Wang
authors: Tingting
authors: T
authors: Zhuang
authors: Magdalena
authors: M
authors: Czarnecka
authors: Michael D
authors: MD
authors: Johnson
authors: Jeffrey A
authors: JA
authors: Toretsky
authors: Joanna
authors: J
authors: Kitlinska
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D009478:Neuropeptide Y / Q000378:metabolism*; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors; D012512:Sarcoma, Ewing / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4