The P2X7 receptor is a key modulator of the PI3K/GSK3β/VEGF signaling network: evidence in experimental neuroblastoma
Neuroblastoma (NB) is an aggressive pediatric tumor, responsible for 15% of cancer-related deaths in childhood, lacking an effective treatment in its advanced stages. The P2X7 receptor for extracellular ATP was associated to NB cell proliferation and recently emerged as a promoter of tumor engraftme...
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| Veröffentlicht in: | Oncogene 2015-10, Vol.34 (41), p.5240-5251 |
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| creator | Amoroso, F Capece, M Rotondo, A Cangelosi, D Ferracin, M Franceschini, A Raffaghello, L Pistoia, V Varesio, L Adinolfi, E |
| description | Neuroblastoma (NB) is an aggressive pediatric tumor, responsible for 15% of cancer-related deaths in childhood, lacking an effective treatment in its advanced stages. The P2X7 receptor for extracellular ATP was associated to NB cell proliferation and recently emerged as a promoter of tumor engraftment, growth and vascularization. In an effort to identify new therapeutic options for neuroblastoma, we studied the role of P2X7 receptor in NB biology. We first analyzed the effect of P2X7 activation or down-modulation of the main biochemical ways involved in NB progression: the PI3K/Akt/GSK3β/MYCN and the HIF1α/VEGF pathways. In ACN human NB cells, P2X7 stimulation enhanced PI3K/Akt, while decreasing GSK3β activity. In the same model, P2X7 silencing or antagonist administration reduced the activity of PI3K/Akt and increased that of GSK3β, leading to a decrease in cellular glycogen stores. Similarly, P2X7 downmodulation caused a reduction in HIF1α levels and vascular endothelial growth factor (VEGF) secretion. Systemic administration of two different P2X7 antagonists (AZ10606120 or A740003) in
nude/nude
mice reduced ACN-derived tumor growth. An even stronger effect of P2X7 blockade was obtained in a syngeneic immune-competent neuroblastoma model: Neuro2A cells injected in
AlbinoJ
mice. Together with tumor regression, treatment with P2X7 antagonists caused downmodulation of the Akt/HIF1α axis, leading to reduced VEGF content and decreased vessel formation. Interestingly, in both experimental models, P2X7 antagonists strongly reduced the expression of the probably best-accepted oncogene in NB:
MYCN
. Finally, we associated P2X7 overexpression with poor prognosis in advanced-stage NB patients. Taken together, our data suggest that P2X7 receptor is an upstream regulator of the main signaling pathways involved in NB growth, metabolic activity and angiogenesis, and a promising therapeutic target for neuroblastoma treatment. |
| doi_str_mv | 10.1038/onc.2014.444 |
| format | Article |
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nude/nude
mice reduced ACN-derived tumor growth. An even stronger effect of P2X7 blockade was obtained in a syngeneic immune-competent neuroblastoma model: Neuro2A cells injected in
AlbinoJ
mice. Together with tumor regression, treatment with P2X7 antagonists caused downmodulation of the Akt/HIF1α axis, leading to reduced VEGF content and decreased vessel formation. Interestingly, in both experimental models, P2X7 antagonists strongly reduced the expression of the probably best-accepted oncogene in NB:
MYCN
. Finally, we associated P2X7 overexpression with poor prognosis in advanced-stage NB patients. Taken together, our data suggest that P2X7 receptor is an upstream regulator of the main signaling pathways involved in NB growth, metabolic activity and angiogenesis, and a promising therapeutic target for neuroblastoma treatment.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2014.444</identifier><identifier>PMID: 25619831</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>1-Phosphatidylinositol 3-kinase ; 13/89 ; 631/67/2332 ; 64 ; 64/60 ; 82/29 ; 82/80 ; 96 ; 96/1 ; 96/95 ; AKT protein ; Angiogenesis ; Animals ; Apoptosis ; Cell Biology ; Cell Line, Tumor ; Cell Proliferation ; Cellular signal transduction ; Children ; Development and progression ; Female ; Genetic aspects ; Glycogen ; Glycogen Synthase Kinase 3 - metabolism ; Glycogen Synthase Kinase 3 beta ; Health aspects ; Human Genetics ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Innovations ; Internal Medicine ; Medicine ; Medicine & Public Health ; Mice, Nude ; Molecular targeted therapy ; Neoplasm Transplantation ; Neuroblastoma ; Neuroblastoma - metabolism ; Oncology ; original-article ; Phosphatidylinositol 3-Kinases - metabolism ; Receptors, Purinergic P2X7 - physiology ; Signal Transduction ; Therapeutic applications ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - metabolism ; Vascularization</subject><ispartof>Oncogene, 2015-10, Vol.34 (41), p.5240-5251</ispartof><rights>Macmillan Publishers Limited 2015</rights><rights>COPYRIGHT 2015 Nature Publishing Group</rights><rights>Macmillan Publishers Limited 2015.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-16d6b3336ed73e2a7325420c940ccc45e0a79870e461aa1b9baf35f507ab3e693</citedby><cites>FETCH-LOGICAL-c526t-16d6b3336ed73e2a7325420c940ccc45e0a79870e461aa1b9baf35f507ab3e693</cites><orcidid>0000-0002-1595-6887 ; 0000-0001-8129-9929</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2014.444$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2014.444$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25619831$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Amoroso, F</creatorcontrib><creatorcontrib>Capece, M</creatorcontrib><creatorcontrib>Rotondo, A</creatorcontrib><creatorcontrib>Cangelosi, D</creatorcontrib><creatorcontrib>Ferracin, M</creatorcontrib><creatorcontrib>Franceschini, A</creatorcontrib><creatorcontrib>Raffaghello, L</creatorcontrib><creatorcontrib>Pistoia, V</creatorcontrib><creatorcontrib>Varesio, L</creatorcontrib><creatorcontrib>Adinolfi, E</creatorcontrib><title>The P2X7 receptor is a key modulator of the PI3K/GSK3β/VEGF signaling network: evidence in experimental neuroblastoma</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Neuroblastoma (NB) is an aggressive pediatric tumor, responsible for 15% of cancer-related deaths in childhood, lacking an effective treatment in its advanced stages. The P2X7 receptor for extracellular ATP was associated to NB cell proliferation and recently emerged as a promoter of tumor engraftment, growth and vascularization. In an effort to identify new therapeutic options for neuroblastoma, we studied the role of P2X7 receptor in NB biology. We first analyzed the effect of P2X7 activation or down-modulation of the main biochemical ways involved in NB progression: the PI3K/Akt/GSK3β/MYCN and the HIF1α/VEGF pathways. In ACN human NB cells, P2X7 stimulation enhanced PI3K/Akt, while decreasing GSK3β activity. In the same model, P2X7 silencing or antagonist administration reduced the activity of PI3K/Akt and increased that of GSK3β, leading to a decrease in cellular glycogen stores. Similarly, P2X7 downmodulation caused a reduction in HIF1α levels and vascular endothelial growth factor (VEGF) secretion. Systemic administration of two different P2X7 antagonists (AZ10606120 or A740003) in
nude/nude
mice reduced ACN-derived tumor growth. An even stronger effect of P2X7 blockade was obtained in a syngeneic immune-competent neuroblastoma model: Neuro2A cells injected in
AlbinoJ
mice. Together with tumor regression, treatment with P2X7 antagonists caused downmodulation of the Akt/HIF1α axis, leading to reduced VEGF content and decreased vessel formation. Interestingly, in both experimental models, P2X7 antagonists strongly reduced the expression of the probably best-accepted oncogene in NB:
MYCN
. Finally, we associated P2X7 overexpression with poor prognosis in advanced-stage NB patients. Taken together, our data suggest that P2X7 receptor is an upstream regulator of the main signaling pathways involved in NB growth, metabolic activity and angiogenesis, and a promising therapeutic target for neuroblastoma treatment.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>13/89</subject><subject>631/67/2332</subject><subject>64</subject><subject>64/60</subject><subject>82/29</subject><subject>82/80</subject><subject>96</subject><subject>96/1</subject><subject>96/95</subject><subject>AKT protein</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cellular signal transduction</subject><subject>Children</subject><subject>Development and progression</subject><subject>Female</subject><subject>Genetic aspects</subject><subject>Glycogen</subject><subject>Glycogen Synthase Kinase 3 - metabolism</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - 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metabolism</topic><topic>Glycogen Synthase Kinase 3 beta</topic><topic>Health aspects</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</topic><topic>Innovations</topic><topic>Internal Medicine</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice, Nude</topic><topic>Molecular targeted therapy</topic><topic>Neoplasm Transplantation</topic><topic>Neuroblastoma</topic><topic>Neuroblastoma - metabolism</topic><topic>Oncology</topic><topic>original-article</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Receptors, Purinergic P2X7 - physiology</topic><topic>Signal Transduction</topic><topic>Therapeutic applications</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>Vascularization</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Amoroso, F</creatorcontrib><creatorcontrib>Capece, M</creatorcontrib><creatorcontrib>Rotondo, A</creatorcontrib><creatorcontrib>Cangelosi, D</creatorcontrib><creatorcontrib>Ferracin, M</creatorcontrib><creatorcontrib>Franceschini, A</creatorcontrib><creatorcontrib>Raffaghello, L</creatorcontrib><creatorcontrib>Pistoia, V</creatorcontrib><creatorcontrib>Varesio, L</creatorcontrib><creatorcontrib>Adinolfi, E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Amoroso, F</au><au>Capece, M</au><au>Rotondo, A</au><au>Cangelosi, D</au><au>Ferracin, M</au><au>Franceschini, A</au><au>Raffaghello, L</au><au>Pistoia, V</au><au>Varesio, L</au><au>Adinolfi, E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The P2X7 receptor is a key modulator of the PI3K/GSK3β/VEGF signaling network: evidence in experimental neuroblastoma</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2015-10-08</date><risdate>2015</risdate><volume>34</volume><issue>41</issue><spage>5240</spage><epage>5251</epage><pages>5240-5251</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Neuroblastoma (NB) is an aggressive pediatric tumor, responsible for 15% of cancer-related deaths in childhood, lacking an effective treatment in its advanced stages. The P2X7 receptor for extracellular ATP was associated to NB cell proliferation and recently emerged as a promoter of tumor engraftment, growth and vascularization. In an effort to identify new therapeutic options for neuroblastoma, we studied the role of P2X7 receptor in NB biology. We first analyzed the effect of P2X7 activation or down-modulation of the main biochemical ways involved in NB progression: the PI3K/Akt/GSK3β/MYCN and the HIF1α/VEGF pathways. In ACN human NB cells, P2X7 stimulation enhanced PI3K/Akt, while decreasing GSK3β activity. In the same model, P2X7 silencing or antagonist administration reduced the activity of PI3K/Akt and increased that of GSK3β, leading to a decrease in cellular glycogen stores. Similarly, P2X7 downmodulation caused a reduction in HIF1α levels and vascular endothelial growth factor (VEGF) secretion. Systemic administration of two different P2X7 antagonists (AZ10606120 or A740003) in
nude/nude
mice reduced ACN-derived tumor growth. An even stronger effect of P2X7 blockade was obtained in a syngeneic immune-competent neuroblastoma model: Neuro2A cells injected in
AlbinoJ
mice. Together with tumor regression, treatment with P2X7 antagonists caused downmodulation of the Akt/HIF1α axis, leading to reduced VEGF content and decreased vessel formation. Interestingly, in both experimental models, P2X7 antagonists strongly reduced the expression of the probably best-accepted oncogene in NB:
MYCN
. Finally, we associated P2X7 overexpression with poor prognosis in advanced-stage NB patients. Taken together, our data suggest that P2X7 receptor is an upstream regulator of the main signaling pathways involved in NB growth, metabolic activity and angiogenesis, and a promising therapeutic target for neuroblastoma treatment.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25619831</pmid><doi>10.1038/onc.2014.444</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-1595-6887</orcidid><orcidid>https://orcid.org/0000-0001-8129-9929</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2015-10, Vol.34 (41), p.5240-5251 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1765955093 |
| source | MEDLINE; SpringerLink Journals; Nature; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | 1-Phosphatidylinositol 3-kinase 13/89 631/67/2332 64 64/60 82/29 82/80 96 96/1 96/95 AKT protein Angiogenesis Animals Apoptosis Cell Biology Cell Line, Tumor Cell Proliferation Cellular signal transduction Children Development and progression Female Genetic aspects Glycogen Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta Health aspects Human Genetics Humans Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Innovations Internal Medicine Medicine Medicine & Public Health Mice, Nude Molecular targeted therapy Neoplasm Transplantation Neuroblastoma Neuroblastoma - metabolism Oncology original-article Phosphatidylinositol 3-Kinases - metabolism Receptors, Purinergic P2X7 - physiology Signal Transduction Therapeutic applications Vascular endothelial growth factor Vascular Endothelial Growth Factor A - metabolism Vascularization |
| title | The P2X7 receptor is a key modulator of the PI3K/GSK3β/VEGF signaling network: evidence in experimental neuroblastoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-20T10%3A11%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20P2X7%20receptor%20is%20a%20key%20modulator%20of%20the%20PI3K/GSK3%CE%B2/VEGF%20signaling%20network:%20evidence%20in%20experimental%20neuroblastoma&rft.jtitle=Oncogene&rft.au=Amoroso,%20F&rft.date=2015-10-08&rft.volume=34&rft.issue=41&rft.spage=5240&rft.epage=5251&rft.pages=5240-5251&rft.issn=0950-9232&rft.eissn=1476-5594&rft_id=info:doi/10.1038/onc.2014.444&rft_dat=%3Cgale_proqu%3EA431726316%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2331632379&rft_id=info:pmid/25619831&rft_galeid=A431726316&rfr_iscdi=true |