Role of p110 isoforms of the class IA phosphoinositide 3-kinases in the pathogenesis of glioblastoma multiforme

Pao Yue-kong Library Electronic Theses Database

Role of p110 isoforms of the class IA phosphoinositide 3-kinases in the pathogenesis of glioblastoma multiforme

 

Author: Luk, Sze-ki, Carina
Title: Role of p110 isoforms of the class IA phosphoinositide 3-kinases in the pathogenesis of glioblastoma multiforme
Degree: M.Phil.
Year: 2010
Subject: Hong Kong Polytechnic University -- Dissertations
Glioblastoma multiforme -- Diagnosis
Department: Dept. of Health Technology and Informatics
Pages: xiv, 124 leaves : ill. (some col.) ; 30 cm.
InnoPac Record: http://library.polyu.edu.hk/record=b2351738
URI: http://theses.lib.polyu.edu.hk/handle/200/5421
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.

Files in this item

Files Size Format
b23517384.pdf 4.683Mb PDF
Copyright Undertaking
As a bona fide Library user, I declare that:
  1. I will abide by the rules and legal ordinances governing copyright regarding the use of the Database.
  2. I will use the Database for the purpose of my research or private study only and not for circulation or further reproduction or any other purpose.
  3. I agree to indemnify and hold the University harmless from and against any loss, damage, cost, liability or expenses arising from copyright infringement or unauthorized usage.
By downloading any item(s) listed above, you acknowledge that you have read and understood the copyright undertaking as stated above, and agree to be bound by all of its terms.

     

Quick Search

Browse

More Information