as-252424 and Brain-Neoplasms

Elevated endogenous phosphoinositide-3-kinase (PI3K) activity is critical for cell proliferation in gliomas. Iron availability is one of the essential factors for cell growth and proliferation. However, any relation between PI3K and cellular iron homeostasis has not been understood so far.. Glioma cells and human primary astrocytes were treated with class I PI3K inhibitors to examine regulation of iron homeostasis components. Regulation of ferritin was detected at mRNA and translational level. Labile iron pool (LIP) and cell proliferation were examined in glioma cells and human primary astrocytes.. Blocking of PI3K activity elevated ferritin level by 6-10 folds in glioma cells by augmenting mRNA expression of ferritin subunits and also by influencing ferritin translation. IRE-IRP interaction was affected due to conversion of IRP1 to cytosolic aconitase that was influenced by increased iron-sulfur scaffold protein iron-sulfur cluster assembly enzyme (ISCU) level. Elevated ferritin sequestered LIP to affect cell proliferation that was reversed in silencing ferritin by siRNAs of ferritin-H and ISCU. Human primary astrocyte with little PI3K activity did not show any change in ferritin level, LIP and cell proliferation by PI3K inhibitors.. PI3K inhibition promotes ferritin synthesis by dual mechanism resulting sequestration of iron to limit its availability for cell proliferation in glioma cells but not in primary astrocytes.. This observation establishes a relation between PI3K signalling and iron homeostasis in glioma cells. It also implies that activated PI3K controls ferritin expression to ensure availability of adequate iron required for cell proliferation.

Topics: Adenine; Animals; Brain Neoplasms; Cell Proliferation; Cells, Cultured; Chromones; Down-Regulation; Ferritins; Glioma; Humans; Iron; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Pyrimidinones; Quinazolines; Rats; Thiazolidinediones; Up-Regulation

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.

Topics: Brain Neoplasms; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Cisplatin; Class Ib Phosphatidylinositol 3-Kinase; Combined Modality Therapy; Down-Regulation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Medulloblastoma; Phosphoinositide-3 Kinase Inhibitors; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; RNA Interference; RNA, Small Interfering; Thiazolidinediones