PMID:22079609

Citation	Luk, SK, Piekorz, RP, Nürnberg, B and Tony To, SS (2012) The catalytic phosphoinositol 3-kinase isoform p110δ is required for glioma cell migration and invasion. Eur. J. Cancer 48:149-57
Abstract	Glioblastoma multiforme (GBM) is a highly invasive and aggressive primary brain tumour in which loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a negative regulator of PI3K signalling, is a common feature. PTEN/PI3K/Akt signalling is involved in the regulation of proliferation, apoptosis and cell migration. Deregulation of PI3K signalling is considered an essential driver in gliomagenesis. However, the role of different PI3K isoforms in glioma is still largely unclear. Here we show that the catalytic PI3K isoform p110δ is consistently expressed at a high level in various glioma cell lines. We used small interfering RNA to selectively deplete p110δ and to determine its tumourigenic roles in PTEN-deficient cells. Interestingly, knockdown of p110δ decreased the cell migration and invasion ability of all GBM cell lines tested. Mechanistically, p110δ knockdown reduced the protein levels of focal adhesion kinase and cell division cycle 42, key regulators of cellular migration. In contrast, pharmacologic inhibition of p110δ by IC87114 or CAL-101 also clearly impaired glioma cell migration but had no obvious effect on the invasion capacity thus pinpointing to possible kinase-dependent and -independent roles of p110δ in glioma pathology. In summary, our data provide novel evidence that in glioma cells p110δ is a key regulator of cell movement and thus may contribute to the highly invasive phenotype of GBM. Isoform specific targeting of PI3Kδ may be beneficial in the treatment of glioblastoma multiforme by specifically inhibiting tumour cell migration capacity.
Links	PubMed Online version:10.1016/j.ejca.2011.09.006
Keywords	Brain Neoplasms/genetics; Brain Neoplasms/pathology; Catalytic Domain/genetics; Catalytic Domain/physiology; Cell Movement/drug effects; Cell Movement/genetics; Cells, Cultured; Class Ia Phosphatidylinositol 3-Kinase/antagonists & inhibitors; Class Ia Phosphatidylinositol 3-Kinase/genetics; Class Ia Phosphatidylinositol 3-Kinase/metabolism; Class Ia Phosphatidylinositol 3-Kinase/physiology; Focal Adhesion Kinase 1/metabolism; Gene Expression Regulation, Neoplastic/drug effects; Gene Knockdown Techniques; Glioma/genetics; Glioma/pathology; Humans; Isoenzymes/genetics; Isoenzymes/metabolism; Neoplasm Invasiveness; RNA, Small Interfering/pharmacology; cdc42 GTP-Binding Protein/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:PK3CD	involved_in	GO:0010628: positive regulation of gene expression	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PK3CD	involved_in	GO:0030335: positive regulation of cell migration	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PK3CD		GO:0030335: positive regulation of cell migration	ECO:0000315:		P		Fig. 3AD, Fig. 5A, and Supplemental Fig. 4A	complete CACAO 3053
HUMAN:PK3CD		GO:0010628: positive regulation of gene expression	ECO:0000315:		P		Fig. 3C	complete CACAO 3054

References

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