Role of Rac1-Mediated Signaling in Medulloblastoma Invasion and Growth

Abstract

Introduction Medulloblastoma, accounting for 25% of pediatric brain tumors, is the most common solid primary tumor of childhood. These tumors display cellular invasion into adjacent parenchyma and subsequently CSF causing metastasis and poor prognosis. The Rac1 GTPase has been shown to be essential for the invasiveness of several tumor types. We therefore investigated Rac1's role in medulloblastoma invasion and growth. Methods Specific depletion of Rac1 was achieved by RNA interference utilizing two independent small interfering RNA (siRNA) oligonucleotides targeted toward Rac1. The activity of MAP kinase pathways was modulated by using specific inhibitors of MEK (U0126), JNK (SP600125), p38 (SB203580), and mTOR (rapamycin). Cell invasion was determined using Matrigel (reconstituted extracellular matrix) transwell invasion chambers. The actin cytoskeleton was visualized using FITC-phalloidin. Results Depletion of Rac1 in DAOY and UW-228 cells inhibits invasion by 70%. Depletion of Rac1 strongly inhibits s...