CB-11 * DIVERSE ROLES FOR RhoA AND RhoC IN GLIOBLASTOMA

Abstract

A number of Rho family members have been shown to control tumor cell proliferation, survival and invasion. Rhophilin, an effector of both RhoA and RhoC, is amplified in glioblastoma and its expression strongly correlates with decreased patient survival. Importantly, rhophilin 2 has recently also been shown to be a critical driver gene of the mesenchymal phenotype in human glioblastoma. However, the cellular functions of RhoA and RhoC in glioblastoma largely remain to be characterized. Here we show that depletion of RhoA, but not RhoC, significantly inhibits glioblastoma cell proliferation. Conversely, depletion of RhoC, but not RhoA, significantly inhibits glioblastoma cell invasion into ex vivo brain slices. In line with this, depletion of RhoC, but not RhoA, also inhibits nuclear squeezing through a 3 mm pore size filter. In addition, we found that depletion of either RhoA or RhoC inhibit glioblastoma cell survival in clonogenic assays. Thus, RhoA and RhoC differentially regulate distinct aspects of the malignant behavior of glioblastoma. We also have identified PDZ-RhoGEF as a critical activator of both RhoA and RhoC in glioblastoma cells, as depletion of this guanine nucleotide exchange factor strongly diminishes serum-stimulated activation of both GTPases. In addition, consistent with the results of depleting either RhoA or RhoC, we showed that depletion of PDZ-RhoGEF, significantly inhibits glioblastoma cell proliferation, invasion and clonogenicity. We also showed that depletion of PDZ-RhoGEF significantly enhances mouse survival in a patient-derived xenograft model.