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rdf:type |
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lifeskim:mentions |
umls-concept:C0025149,
umls-concept:C0035820,
umls-concept:C0044602,
umls-concept:C0205314,
umls-concept:C0285761,
umls-concept:C0430054,
umls-concept:C0596290,
umls-concept:C0597298,
umls-concept:C0679622,
umls-concept:C1136031,
umls-concept:C1150481,
umls-concept:C1368105,
umls-concept:C1424600,
umls-concept:C1451005,
umls-concept:C1705053,
umls-concept:C1705325
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pubmed:issue |
7
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pubmed:dateCreated |
2011-7-20
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pubmed:abstractText |
Medulloblastoma is the most common malignant brain tumor in children and is associated with a poor outcome. We were interested in gaining further insight into the potential of targeting the human kinome as a novel approach to sensitize medulloblastoma to chemotherapeutic agents. A library of small interfering RNA (siRNA) was used to downregulate the known human protein and lipid kinases in medulloblastoma cell lines. The analysis of cell proliferation, in the presence or absence of a low dose of cisplatin after siRNA transfection, identified new protein and lipid kinases involved in medulloblastoma chemoresistance. PLK1 (polo-like kinase 1) was identified as a kinase involved in proliferation in medulloblastoma cell lines. Moreover, a set of 6 genes comprising ATR, LYK5, MPP2, PIK3CG, PIK4CA, and WNK4 were identified as contributing to both cell proliferation and resistance to cisplatin treatment in medulloblastoma cells. An analysis of the expression of the 6 target genes in primary medulloblastoma tumor samples and cell lines revealed overexpression of LYK5 and PIK3CG. The results of the siRNA screen were validated by target inhibition with specific pharmacological inhibitors. A pharmacological inhibitor of p110? (encoded by PIK3CG) impaired cell proliferation in medulloblastoma cell lines and sensitized the cells to cisplatin treatment. Together, our data show that the p110? phosphoinositide 3-kinase isoform is a novel target for combinatorial therapies in medulloblastoma.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/5-(5-(4-fluoro-2-hydroxyphenyl)furan...,
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cisplatin,
http://linkedlifedata.com/resource/pubmed/chemical/Class Ib Phosphatidylinositol...,
http://linkedlifedata.com/resource/pubmed/chemical/PIK3CG protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/Thiazolidinediones,
http://linkedlifedata.com/resource/pubmed/chemical/emt protein-tyrosine kinase,
http://linkedlifedata.com/resource/pubmed/chemical/polo-like kinase 1
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1557-3125
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pubmed:author |
pubmed-author:ArcaroAlexandreA,
pubmed-author:AtamerAbdullahA,
pubmed-author:DelattreOlivierO,
pubmed-author:ElsingAlexandra NAN,
pubmed-author:FattetSarahS,
pubmed-author:GrotzerMichael AMA,
pubmed-author:GuerreiroAna SAS,
pubmed-author:JacksonShaun PSP,
pubmed-author:KuleszaDorota WDW,
pubmed-author:SchoenwaelderSimone MSM,
pubmed-author:ShalabyTarekT
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pubmed:copyrightInfo |
©2011 AACR.
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pubmed:issnType |
Electronic
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pubmed:volume |
9
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
925-35
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pubmed:meshHeading |
pubmed-meshheading:21652733-Brain Neoplasms,
pubmed-meshheading:21652733-Cell Cycle Proteins,
pubmed-meshheading:21652733-Cell Line, Tumor,
pubmed-meshheading:21652733-Cell Proliferation,
pubmed-meshheading:21652733-Cells, Cultured,
pubmed-meshheading:21652733-Cisplatin,
pubmed-meshheading:21652733-Class Ib Phosphatidylinositol 3-Kinase,
pubmed-meshheading:21652733-Combined Modality Therapy,
pubmed-meshheading:21652733-Down-Regulation,
pubmed-meshheading:21652733-Drug Resistance, Neoplasm,
pubmed-meshheading:21652733-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:21652733-Humans,
pubmed-meshheading:21652733-Medulloblastoma,
pubmed-meshheading:21652733-Protein-Serine-Threonine Kinases,
pubmed-meshheading:21652733-Protein-Tyrosine Kinases,
pubmed-meshheading:21652733-Proto-Oncogene Proteins,
pubmed-meshheading:21652733-RNA, Small Interfering,
pubmed-meshheading:21652733-RNA Interference,
pubmed-meshheading:21652733-Thiazolidinediones
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pubmed:year |
2011
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pubmed:articleTitle |
A sensitized RNA interference screen identifies a novel role for the PI3K p110? isoform in medulloblastoma cell proliferation and chemoresistance.
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pubmed:affiliation |
Department of Oncology, University Children's Hospital, Zurich, Switzerland.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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