Abstract LB-516: PDZ-RhoGEF promotes glioblastoma cell invasion, proliferation and survival

Abstract

Abstract Invasion of glioblastoma cells into the surrounding brain parenchyma is a critical parameter of this disease as it hampers complete surgical resection of the tumor mass. Glioblastoma tumors are highly proliferative and resistant to radio- and chemo-therapy, thereby leading to tumor recurrence. Rho family members have been shown to control both the invasive and proliferative behavior of tumor cells. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs). In this study we focused on PDZ-RhoGEF, as its role in glioblastoma is not known. It has been shown that invading glioblastoma cells need contractile force to squeeze their nucleus through narrow spaces that are characteristic of the brain parenchyma (Beadle et al, Mol. Biol. Cell (2008) 19: 3357). We found that depletion of PDZ-RhoGEF in U87 and SNB19 glioblastoma cells strongly inhibits cell migration across a small (3 μm) pore size filter, a process which necessitates nuclear squeezing. PDZ-RhoGEF depletion also inhibits cell migration across a larger (8 μm) pore size filter, albeit to a lesser extent than in the squeezing assay. Interestingly, cells lacking PDZ-RhoGEF display multi-lobed lamellae, suggesting a defect in cell polarization. In addition, PDZ-RhoGEF depletion strongly inhibits glioblastoma cell invasion into ex vivo brain slices. In vitro studies have demonstrated that PDZ-RhoGEF can act on both RhoA and RhoC. The roles of these GTPases in the invasive behavior of glioblastoma have not been reported to date. Interestingly, we found that depletion of RhoC strongly inhibits brain slice invasion and nuclear squeezing, whereas depletion of RhoA has no significant effect on these functions. Thus, taken together, these data suggest that PDZ-RhoGEF largely acts by activating RhoC to stimulate glioma cell invasion. Our preliminary data also indicate that PDZ-RhoGEF mediates glioma cell proliferation and survival. In conclusion, our findings suggest that PDZ-RhoGEF is a potential therapeutic target for glioma therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-516. doi:1538-7445.AM2012-LB-516