Fn14 Induced Glioma Cell Survival is Dependent upon Akt2 Function
Fortin, Shannon P. 1,2; Tran, Nhan L.2; Drake, Kelsey L.2,3; Savitch, Benjamin A.2; Ennis, Matthew J.1,2; Winkles, Jeffrey A.4; Loftus, Joseph C.5; and Berens, Michael E.2
1Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ; 2Cancer and Cell Biology Division; Translational Genomics Research Institute, Phoenix, AZ; 3School of Life Sciences, Arizona State University, Tempe, AZ; 4Departments of Surgery and Physiology and the Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD; 5Mayo Clinic Arizona, Scottsdale, AZ
The invasiveness of gliomas is largely responsible for failed resections and resistance to current chemo- and radiation-therapies. We have shown that the transmembrane receptor, fibroblast growth factor-inducible 14 (Fn14) signals to stimulate glioma cell survival via the NF_B-mediated up-regulation of BCL-XL and BCL-W mRNA expression (Tran et al. JBC 2005). Here, we show that activation of the TWEAK-Fn14 ligand-receptor system leads to rapid stabilization of BCL-XL and BCL-W proteins via suppression of the pro-apoptotic BAD protein function. Phosphorylation of BAD on serine 136 follows Fn14 activation, and is dependent on Akt signaling. Activation of Fn14 results in phosphorylation of both Akt1 and Akt2. However, siRNA-mediated depletion of Akt1 and Akt2 showed that BAD serine 136 phosphorylation is dependent specifically on Akt2 function. Depletion of Akt2 expression by siRNA also abrogates Fn14-induced glioma cell survival, whereas no effect on glioma cell survival was observed in siRNA-mediated depletion of Akt1 expression. Interestingly, expression levels of both Fn14 and Akt2 mRNA correlate with glial tumor grade and with survival duration of patients with glial tumors. We hypothesize that the Fn14 protein functions, in part, to enhance invasive glioblastoma cell survival by activation of Akt2. Understanding the function and signaling of the TWEAK-Fn14 ligand-receptor system may lead to development of novel therapies to therapeutically target invasive glioma cells.