Cooperative Regulation Between Proliferative Signals By Activated Ras And Inhibitors Of Apoptosis (Iaps) In Gliomagenesis

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Transformation requires not only aberrant proliferation through signaling pathways such as activated Ras as demonstrated by our lab in GBMs, but also aberrant inhibition of regulators of apoptosis. Towards the latter, little is known about the expression and function of a family of proteins known as Inhibitors of Apoptosis Proteins (IAPs), which includes cIAP1, cIAP2, XIAP and Survivin, in GBMs. Human tumors which are prevalent in activating Ras mutations, such as colon and pancreatic cancers, produce high amounts of Survivin. We hypothesize that elevated activity of Ras in GBMs, as previously described by us, leads to aberrant expression of IAPs in GBMs and through its anti-apoptotic functions plays a role in glioma transformation. Our previously described GFAP:12V-HaRas (RasB8) transgenic mouse glioma model was utilized. Elevated expression of activated Ras in the mouse gliomas was accompanied with increased expression of XIAP and Survivin. This was also prevalent in expression in human GBM cells, with elevated Ras activity. Knockdown of Ha-Ras in human and mouse GBM cells, by transfecting with couple of siRNA targeted against Ha-Ras gene, significantly decreased XIAP and Survivin levels. Knockdown of Ha-Ras in the mouse and human GBM cells increased their sensitivity to apoptosis inducing chemotherapy. Current experiments include a genetic approach to down regulate Ras activity, by expression of a dominant-negative form of the Ha-Ras (Ha-Ras N17), in GBM cells and evaluating regulation of XIAP and Survivin expression. These experiments will be complemented with farnesyl transferase inhibitors to also inhibit Ras activity in the glioma cells. A Tet-inducible strategy to over express activated Ha-Ras in both transformed and non-transformed mouse and human astrocytes is being undertaken. These in vitro studies will be complemented by in vivo studies involving breeding our RasB8 glioma model to double transgenics with GFAP-Cre regulated decreased expression of Survivinflox/flox in astrocytes, with a postulated decrease in gliomagenic potential. The results to date and those underway are highly suggestive of the thesis that elevated Ras activity leads to glial transformation by not only mitogenic signals, but also by cooperative expression of anti-apoptotic proteins, such as IAPS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 123.