Although GPX is known as a

Although GPX2 is known as a gastrointestinal GSH peroxidase, it also is expressed in other tissues (Brigelius-Flohé and Kipp, 2012). Interestingly, its expression level is increased in intestinal crypt stem cells and malignant epithelial cells, suggesting a role in proliferation and self-renewal. It also was found that GPX2 overexpression alleviates the apoptotic response of breast cancer cells to oxidative stress (Yan and Chen, 2006). The GPX2 promoter is activated by the Wnt pathway that is highly active in iPSCs and ESCs (Kipp et al., 2012). Like many antioxidant enzymes, GPX2 expression is further controlled by transcription factor NRF2 (Banning et al., 2005), which very recently has been implicated also in the self-renewal capacity of ESCs (Jang et al., 2014). It is thus conceivable that the high antioxidant defense of iPSCs is not only involved in genomic stability, but also required for self-renewal, replicative immortality, and the delay of differentiation of iPSCs.
Experimental Procedures
Author Contributions
Acknowledgments
Introduction Glioblastoma (GBM) is the most common primary malignant adenylyl cyclase tumor in adults. Despite multimodal aggressive therapies, survival of a vast majority of the patients is less than 2 years with the 5-year survival rate as low as 5% (Stupp et al., 2009). Previous efforts in the development of therapeutics for GBM have largely depended on studies with conventional GBM cell lines. While providing some benefits, genetic and phenotypic drift is inevitable in these long-term in vitro cell cultures. Importantly, the standard GBM cell lines cannot recapitulate the heterogeneous cellular populations of GBM (Ernst et al., 2009; Lee et al., 2006). These limitations may partially explain the large gap between promising in vitro data and disappointing GBM clinical trial outcomes. The identification of effective therapeutics has been hindered, in part, by the lack of more clinically relevant GBM models. Tumor-initiating GBM stem-like cells (GSCs) isolated from patients propagate the heterogeneity of the original GBMs in immunocompromised mice and preserve specific genetic alterations found in the original tumor (Hemmati et al., 2003; Singh et al., 2004). In the past decade, transcriptomic and methylation analyses have classified GBM tumors into several subtypes (Phillips et al., 2006; Sturm et al., 2012; Verhaak et al., 2010), including proneural (PN), classical, and mesenchymal (MES) GBMs. While these signatures are based on the predominant gene expression patterns in the tumor and correlate with mutation and epigenetic status, GBMs are very heterogeneous, and data demonstrate the presence of cells of multiple subtypes within a single tumor as well as transitions between subtypes (Bhat et al., 2013; Patel et al., 2014; Piao et al., 2013). Our work has classified the majority of GSCs as MES or PN based on transcriptomic signatures. In comparison to PN GSCs, MES GSCs display highly aggressive and radioresistant phenotypes (Mao et al., 2013). The core MES GSC gene signature also correlates with poor GBM patient prognosis, indicating the importance of understanding molecular mechanisms driving MES-specific biology. These patient-derived and subtype-specific GSCs provide a powerful model for the heterogeneous human disease and future therapy development. Kinases are often activated in cancer, indicating the potential of kinase inhibitors for cancer therapy. Kinases control a wide variety of cell functions related to tumorigenesis, including survival/apoptosis, cell-cycle progression/proliferation, stem cell maintenance, DNA damage repair, cell motility/invasion, and therapeutic resistance. Indeed, the discovery of oncogenic kinases and development of target-specific inhibitors have already revolutionized the treatment of certain groups of cancers, exemplified by the success of Gleevec for chronic myeloid leukemia (Druker et al., 2001). Protein kinases are now firmly established as a major class of anti-cancer therapeutic targets. There has been an explosion in the number of kinase inhibitors that have successfully entered the clinic or have produced promising data in preclinical drug development pipelines (Zhang et al., 2009). While such success has not yet been achieved for GBM, identification of kinases whose inhibition attenuates GSC properties may pave the way toward novel therapeutics (Mellinghoff et al., 2012).