PMID- 25132261
OWN - NLM
STAT- MEDLINE
DCOM- 20150826
LR  - 20211021
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 34
IP  - 24
DP  - 2015 Jun 11
TI  - Neuropeptide Y receptor Y5 as an inducible pro-survival factor in neuroblastoma: 
      implications for tumor chemoresistance.
PG  - 3131-43
LID - 10.1038/onc.2014.253 [doi]
AB  - Neuroblastoma (NB) is a pediatric tumor of neural crest origin with heterogeneous 
      phenotypes. Although low-stage tumors carry a favorable prognosis, >50% of 
      high-risk NB relapses after treatment with a fatal outcome. Thus developing 
      therapies targeting refractory NB remains an unsolved clinical problem. 
      Brain-derived neurotrophic factor (BDNF) and its TrkB receptor are known to 
      protect NB cells from chemotherapy-induced cell death, while neuropeptide Y 
      (NPY), acting via its Y2 receptor (Y2R), is an autocrine proliferative and 
      angiogenic factor crucial for maintaining NB tumor growth. Here we show that in 
      NB cells, BDNF stimulates the synthesis of NPY and induces expression of another 
      one of its receptors, Y5R. In human NB tissues, the expression of NPY and Y5R 
      positively correlated with the expression of BDNF and TrkB. Functionally, BDNF 
      triggered Y5R internalization in NB cells, whereas Y5R antagonist inhibited 
      BDNF-induced p44/42 mitogen-activated protein kinase activation and its 
      pro-survival activity. These observations suggested TrkB-Y5R transactivation that 
      resulted in cross-talk between their signaling pathways. Additionally, NPY and 
      Y5R were upregulated in a BDNF-independent manner in NB cells under pro-apoptotic 
      conditions, such as serum deprivation and chemotherapy, as well as in cell lines 
      and tissues derived from posttreatment NB tumors. Blocking Y5R in chemoresistant 
      NB cells rich in this receptor sensitized them to chemotherapy-induced apoptosis 
      and inhibited their growth in vivo by augmenting cell death. In summary, the 
      NPY/Y5R axis is an inducible survival pathway activated in NB by BDNF or cellular 
      stress. Upon such activation, Y5R augments the pro-survival effect of BDNF via 
      its interactions with TrkB receptor and exerts an additional BDNF-independent 
      anti-apoptotic effect, both of which contribute to NB chemoresistance. Therefore, 
      the NPY/Y5R pathway may become a novel therapeutic target for patients with 
      refractory NB, thus far an incurable form of this disease.
FAU - Czarnecka, M
AU  - Czarnecka M
AD  - Department of Biochemistry and Molecular and Cellular Biology, Georgetown 
      University Medical Center, Georgetown University, Washington, DC, USA.
FAU - Trinh, E
AU  - Trinh E
AD  - Department of Biochemistry and Molecular and Cellular Biology, Georgetown 
      University Medical Center, Georgetown University, Washington, DC, USA.
FAU - Lu, C
AU  - Lu C
AD  - McGovern Institute, Massachusetts Institute of Technology, Boston, MA, USA.
FAU - Kuan-Celarier, A
AU  - Kuan-Celarier A
AD  - Department of Biochemistry and Molecular and Cellular Biology, Georgetown 
      University Medical Center, Georgetown University, Washington, DC, USA.
FAU - Galli, S
AU  - Galli S
AD  - Department of Biochemistry and Molecular and Cellular Biology, Georgetown 
      University Medical Center, Georgetown University, Washington, DC, USA.
FAU - Hong, S-H
AU  - Hong SH
AD  - Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown 
      University Medical Center, Georgetown University, Washington, DC, USA.
FAU - Tilan, J U
AU  - Tilan JU
AD  - 1] Department of Nursing, School of Nursing and Health Studies, Georgetown 
      University, Washington, DC, USA [2] Department of Human Science, School of 
      Nursing and Health Studies, Georgetown University, Washington, DC, USA.
FAU - Talisman, N
AU  - Talisman N
AD  - Department of Biochemistry and Molecular and Cellular Biology, Georgetown 
      University Medical Center, Georgetown University, Washington, DC, USA.
FAU - Izycka-Swieszewska, E
AU  - Izycka-Swieszewska E
AD  - Department of Pathology and Neuropathology, Medical University of Gdansk, Gdansk, 
      Poland.
FAU - Tsuei, J
AU  - Tsuei J
AD  - Department of Biochemistry and Molecular and Cellular Biology, Georgetown 
      University Medical Center, Georgetown University, Washington, DC, USA.
FAU - Yang, C
AU  - Yang C
AD  - Department of Biochemistry and Molecular and Cellular Biology, Georgetown 
      University Medical Center, Georgetown University, Washington, DC, USA.
FAU - Martin, S
AU  - Martin S
AD  - Department of Human Science, School of Nursing and Health Studies, Georgetown 
      University, Washington, DC, USA.
FAU - Horton, M
AU  - Horton M
AD  - Department of Human Science, School of Nursing and Health Studies, Georgetown 
      University, Washington, DC, USA.
FAU - Christian, D
AU  - Christian D
AD  - Department of Human Science, School of Nursing and Health Studies, Georgetown 
      University, Washington, DC, USA.
FAU - Everhart, L
AU  - Everhart L
AD  - Department of Biochemistry and Molecular and Cellular Biology, Georgetown 
      University Medical Center, Georgetown University, Washington, DC, USA.
FAU - Maheswaran, I
AU  - Maheswaran I
AD  - Department of Biochemistry and Molecular and Cellular Biology, Georgetown 
      University Medical Center, Georgetown University, Washington, DC, USA.
FAU - Kitlinska, J
AU  - Kitlinska J
AD  - Department of Biochemistry and Molecular and Cellular Biology, Georgetown 
      University Medical Center, Georgetown University, Washington, DC, USA.
LA  - eng
GR  - 1R01CA123211/CA/NCI NIH HHS/United States
GR  - P30-CA051008/CA/NCI NIH HHS/United States
GR  - UL1 RR031975/RR/NCRR NIH HHS/United States
GR  - UL1 TR000101/TR/NCATS NIH HHS/United States
GR  - UL1RR031975/RR/NCRR NIH HHS/United States
GR  - P30 CA051008/CA/NCI NIH HHS/United States
GR  - R03 CA178809/CA/NCI NIH HHS/United States
GR  - 1R03CA178809/CA/NCI NIH HHS/United States
GR  - UL1TR000101/TR/NCATS NIH HHS/United States
GR  - R01 CA123211/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140818
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Neuropeptide Y)
RN  - 0 (Receptors, Neuropeptide Y)
RN  - 0 (neuropeptide Y5 receptor)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*therapeutic use
MH  - Apoptosis/drug effects/genetics
MH  - Cell Survival/drug effects/genetics
MH  - Cells, Cultured
MH  - Child
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Neuroblastoma/*drug therapy/genetics/*pathology
MH  - Neuropeptide Y/pharmacology/*physiology
MH  - Receptors, Neuropeptide Y/*physiology
PMC - PMC4333135
MID - NIHMS607462
COIS- Conflict of interest: The authors declare no conflict of interest.
EDAT- 2014/08/19 06:00
MHDA- 2015/08/27 06:00
PMCR- 2015/12/11
CRDT- 2014/08/19 06:00
PHST- 2014/03/14 00:00 [received]
PHST- 2014/05/19 00:00 [revised]
PHST- 2014/06/20 00:00 [accepted]
PHST- 2014/08/19 06:00 [entrez]
PHST- 2014/08/19 06:00 [pubmed]
PHST- 2015/08/27 06:00 [medline]
PHST- 2015/12/11 00:00 [pmc-release]
AID - onc2014253 [pii]
AID - 10.1038/onc.2014.253 [doi]
PST - ppublish
SO  - Oncogene. 2015 Jun 11;34(24):3131-43. doi: 10.1038/onc.2014.253. Epub 2014 Aug 
      18.