Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.1604
Title: Hypoxia shifts activity of neuropeptide Y in Ewing sarcoma from growth-inhibitory to growth-promoting effects
Authors: Tilan, J.U
Lu, C
Galli, S
Izycka-Swieszewska, E
Earnest, J.P
Shabbir, A 
Everhart, L.M
Wang, S
Martin, S
Horton, M
Mahajan, A
Christian, D
O'Neill, A
Wang, H
Zhuang, T
Czarnecka, M
Johnson, M.D
Toretsky, J.A
Kitlinska, J
Keywords: aldehyde dehydrogenase
dipeptidyl peptidase IV
neuropeptide Y
neuropeptide Y [3-36]
neuropeptide Y1 receptor
neuropeptide Y2 receptor
neuropeptide Y5 receptor
unclassified drug
animal experiment
animal model
animal tissue
article
cancer growth
cancer inhibition
cancer stem cell
carcinogenesis
cell migration
cell proliferation
cell stimulation
clinical article
controlled study
enzyme activity
Ewing sarcoma
human
human cell
human tissue
hypoxia
mouse
nonhuman
protein analysis
protein expression
protein function
protein induction
protein secretion
receptor binding
sarcoma cell
tumor vascularization
Animals
Cell Growth Processes
Cell Hypoxia
Cell Line, Tumor
Dipeptidyl Peptidase 4
Heterografts
Humans
Mice
Mice, Nude
Mice, SCID
Neoplastic Stem Cells
Neovascularization, Pathologic
Neuropeptide Y
Receptors, Neuropeptide Y
Sarcoma, Ewing
Issue Date: 2013
Publisher: Impact Journals LLC
Citation: Tilan, J.U, Lu, C, Galli, S, Izycka-Swieszewska, E, Earnest, J.P, Shabbir, A, Everhart, L.M, Wang, S, Martin, S, Horton, M, Mahajan, A, Christian, D, O'Neill, A, Wang, H, Zhuang, T, Czarnecka, M, Johnson, M.D, Toretsky, J.A, Kitlinska, J (2013). Hypoxia shifts activity of neuropeptide Y in Ewing sarcoma from growth-inhibitory to growth-promoting effects. Oncotarget 4 (12) : 2487-2501. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.1604
Rights: Attribution 4.0 International
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.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/177782
ISSN: 19492553
DOI: 10.18632/oncotarget.1604
Rights: Attribution 4.0 International
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