title: A sensitized RNA interference screen identifies a novel role for the PI3K p110γ isoform in medulloblastoma cell proliferation and chemoresistance.
abstract: 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 p110γ (encoded by PIK3CG) impaired cell proliferation in medulloblastoma cell lines and sensitized the cells to cisplatin treatment. Together, our data show that the p110γ phosphoinositide 3-kinase isoform is a novel target for combinatorial therapies in medulloblastoma.
authors.affiliation: Department of Oncology, University Children's Hospital, Zurich, Switzerland.
authors.forename: Ana S
authors.initials: AS
authors.lastname: Guerreiro
authors.forename: Sarah
authors.initials: S
authors.lastname: Fattet
authors.forename: Dorota W
authors.initials: DW
authors.lastname: Kulesza
authors.forename: Abdullah
authors.initials: A
authors.lastname: Atamer
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Elsing
authors.forename: Tarek
authors.initials: T
authors.lastname: Shalaby
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
authors.forename: Simone M
authors.initials: SM
authors.lastname: Schoenwaelder
authors.forename: Michael A
authors.initials: MA
authors.lastname: Grotzer
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Alexandre
authors.initials: A
authors.lastname: Arcaro
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D002945:Cisplatin / Q000627:therapeutic use; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics*; D003131:Combined Modality Therapy; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D002945:Cisplatin; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D000097869:Polo-Like Kinase 1; C512438:5-(5-(4-fluoro-2-hydroxyphenyl)furan-2-ylmethylene)thiazolidine-2,4-dione; C546760:PIK3CG protein, human; C080813:emt protein-tyrosine kinase