Inactivation of Lgl1 in Glioblastoma

Title: Inactivation of Lgl1 in Glioblastoma
Authors: Gont, Alexander
Date: 2016
Abstract: Glioblastoma is the most aggressive and invasive adult brain cancer. In glioblastoma, the loss of the tumour suppressor PTEN is the most common genetic alteration resulting in aberrant activation of the PI3-kinase pathway. In Drosophila, the loss of tumour suppressor Lgl results in massive overgrowth of brain tissue that is highly invasive when transplanted into wildtype hosts. Subsequent study of Lgl protein function revealed that it is important for maintenance of cell polarity and neuroblast differentiation through asymmetric cell divisions. It is unclear if inactivation of Lgl occurs in human brain cancers and what role it plays in glioblastoma malignancy. Firstly, this study demonstrated that the loss of PTEN leads to inactivation of Lgl1 via phosphorylation by atypical protein kinase C iota (PKCι). In primary glioblastoma cultures, preventing Lgl1 inactivation by either PTEN expression, PKCι knockdown or expression of non-phosphorylatable Lgl (Lgl3SA) promoted differentiation. In a follow-up study, the effect of active Lgl1 in glioblastoma invasion was investigated. Lgl3SA expression inhibited invasion in vitro through decreased motility. In an orthotopic xenograft mouse model using primary glioblastoma cells, Lgl3SA expression promoted differentiation and decreased invasion. Therefore, PTEN loss, acting via PKCι and Lgl1, has a key role in maintaining glioblastoma in an undifferentiated, highly invasive state similar to what is observed following Lgl loss in Drosophila. PREX1 was investigated as a potential link between PTEN loss and activation of PKCι. PREX1, a Rac activator, is synergistically activated by the PI3-kinase product PIP3 and G protein-coupled receptor (GPCR) βγ subunits. PREX1 expression was detected in primary glioblastoma cell cultures as well as the majority of patient tumour samples. Both PI3-kinase and GPCR βγ subunit activity is required for PREX1 to promote invasion in glioblastoma. In primary glioblastoma cells, Rac1 preferentially associated with Par6a leading to activation of PKCι. Knockdown of PREX1 decreased activation of PKCι. Thus, PREX1 stimulates PKCι activity in glioblastoma likely by modulating the Rac1/Par6a/PKCι complex. The PI3-kinase pathway is activated by mutation in most glioblastomas and these results show this requires a context of GPCR signalling to promote invasion.
CollectionThèses, 2011 - // Theses, 2011 -