Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/3528
Title: Role of p110 isoforms of the class IA phosphoinositide 3-kinases in the pathogenesis of glioblastoma multiforme
Authors: Luk, Sze-ki, Carina
Keywords: Hong Kong Polytechnic University -- Dissertations
Glioblastoma multiforme -- Diagnosis
Issue Date: 2010
Publisher: The Hong Kong Polytechnic University
Abstract: Glioblastoma multiforme (GBM) is a highly invasive and aggressive primary brain tumour in which loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function is a common feature. PTEN acts as a tumour suppressor by inhibiting the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway through dephosphorylation of phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3). PTEN/PI3K/Akt thus constitutes an important signalling pathway regulating various cellular responses including cell proliferation, cell growth, metabolism, apoptosis and migration. Loss of PTEN function causes accumulation of PtdIns(3,4,5)P3 mimicking the effect of PI3K activation leading to the induction of its downstream effectors. Deregulation of the PI3K signalling pathway is considered an essential driver in gliomagenesis. However, the role of different PI3K isoforms in glioma is still largely unclear. In this study, we used small interfering RNAs (siRNA) to selectively inactivate the three Class IA PI3K isoforms, p110α, p110β and p110δ, to determine their tumorigenic roles in PTEN-deficient U-87MG glioma cells. Surprisingly, depletion of p110α did not have any effect on both signalling and cellular functional responses. In contrast, downregulation of p110β resulted in significant inhibition of glioma cell proliferation and G1 cell cycle arrest. Interestingly, the protein levels of phospho-Akt were increased. Knockdown of p110β also induced increased expression of cyclin D1 and p27. Cyclin D1 plays a rate-limiting role in cell cycle progression during mid G1 phase, whereas p27 acts as a negative regulator of cyclin and cyclin-dependent kinase (CDK) activity to arrest cells before they enter into S phase. These findings suggested that p110β is involved in cell cycle progression thereby regulating tumour proliferation. On the other hand, downregulation of the p110δ isoform resulted in reduced cell migration and invasion, but only exhibited slight inhibition on cell proliferation. p110δ knockdown reduced the expression of focal adhesion kinase (FAK) and cell division cycle 42 (cdc42). In contrast to p110β knockdown, reduction in p110δ resulted in increased expression of cyclin-dependent kinase 6 (CDK6) and decreased expression of p27. Since decreased level of p27 enhances G1 to S phase transition, proliferation will continue in glioma cells. These observations suggested that p110δ is mainly involved in cell movement rather than in cell growth. Taken together, our findings further support the need for the development of isoform-specific PI3K inhibitors for the treatment of glioblastoma multiforme.
Description: xiv, 124 leaves : ill. (some col.) ; 30 cm.
PolyU Library Call No.: [THS] LG51 .H577M HTI 2010 Luk
URI: http://hdl.handle.net/10397/3528
Rights: All rights reserved.
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