The catalytic phosphoinositol 3-kinase isoform p110δ is required for glioma cell migration and invasion.

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.

• Authors: Sze Ki Luk, Roland P Piekorz, Bernd Nürnberg, Shing-Shun Tony To
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 48 Issue 1 Pg. 149-57 (Jan 2012) ISSN: 1879-0852 [Electronic] England
• PMID: 22079609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Isoenzymes
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Small Interfering
• Class Ia Phosphatidylinositol 3-Kinase
• Focal Adhesion Kinase 1
• PTK2 protein, human
• cdc42 GTP-Binding Protein

Topics

• Brain Neoplasms (genetics, pathology)
• Catalytic Domain (genetics, physiology)
• Cell Movement (drug effects, genetics)
• Cells, Cultured
• Class Ia Phosphatidylinositol 3-Kinase (genetics, metabolism, physiology)
• Focal Adhesion Kinase 1 (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Glioma (genetics, pathology)
• Humans
• Isoenzymes (genetics, metabolism)
• Neoplasm Invasiveness
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Small Interfering (pharmacology)
• cdc42 GTP-Binding Protein (metabolism)