Regulation of glioblastoma cell invasion by PKCi and RhoB

• Published in: Oncogene Vol. 27; no. 25; pp. 3587 - 3595
• Main Authors: BALDWIN, R. M, PAROLIN, D. A. E, LORIMER, I. A. J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 05.06.2008
• Subjects: Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Fundamental and applied biological sciences. Psychology; Medical sciences; Molecular and cellular biology; Neurology; Tumors of the nervous system. Phacomatoses; Nervous system diseases; Enzyme; Transferases; Glioblastoma; PTEN; Malignant tumor; Carcinogenesis; RhoB; Malignant glioma; Regulation(control); atypical PKC; Kinase; Central nervous system disease; PI 3-kinase; Cancer; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1211027

Glioblastoma multiforme is the most aggressive form of primary brain tumor and remains largely incurable, in large part, due to its highly invasive nature. The phosphoinositide (PI) 3-kinase pathway is often constitutively active in these tumors due to activating mutations in the epidermal growth factor receptor, or deletion/loss of function of the tumor suppressor PTEN. Protein kinase C type i (PKCi), a member of the atypical protein kinase C family, is activated by the PI 3-kinase pathway and is an important downstream mediator. Here, we have assessed the role of PKCi in glioblastoma cell invasion. Depletion of PKCi with RNA interference caused an increase in actin stress fibers and a decrease in cell motility and invasion. Gene expression microarray analysis of U87MG cells showed that PKCi repressed expression of mRNA for RhoB, which has previously been shown to have a role in actin stress fiber formation. Western blot analysis showed that both PKCi depletion and pharmacological inhibition of PKCi caused an increase in the protein levels of RhoB, as did inhibition of PI 3-kinase. Expression of RhoB from a constitutive promoter caused changes in actin stress fibers and cell invasion that were similar to those seen with PKCi depletion. These data show that PKCi, activated as a consequence of aberrant upstream PI 3-kinase signaling, mediates glioblastoma cell motility and invasion, and that repression of RhoB is key downstream event in PKCi signaling leading to enhanced cell motility. In addition, constitutive expression of RhoB repressed PKCi activity, as assessed by its phosphorylation status on Thr555. PKCi and RhoB are, therefore, mutually antagonistic, potentially creating a sensitive switch between invasive and non-invasive phenotypes.Oncogene (2008) 27, 3587-3595; doi:10.1038/sj.onc.1211027; published online 21 January 2008