ABSTRACT
Glutathione peroxidase 2 (GPx2) was first described in 1993 (Chu et al., 1993) and belongs to a family of hydroperoxide-reducing thiolperoxidases. The whole family consists of eight isoforms of which five are known to be selenoproteins in humans (For an overview, see Brigelius-Flohé and Maiorino, 2013). GPx2 has a high sequence homology with GPx1. Both use glutathione (GSH) to reduce H2O2 and soluble organic hydroperoxides, but GPx2 is supposed to have a stronger preference for organic hydroperoxides (Chu et al., 1993). So far, no purified GPx2 has been available to convincingly identify its specific substrates or kinetic constants. However, unlike the ubiquitously expressed GPx1, GPx2 is epithelium-specific with a predominant expression in epithelial cells lining the whole gastrointestinal tract as well as in breast, bladder, and lung epithelium (Cho et al., 2002; Chu et al., 1993, 1999; Florian et al., 2001; Komatsu et al., 2001). In the intestinal epithelium, GPx2 is not uniformly expressed but rather shows a gradient with high expression at the base of intestinal crypts and lower expression in villi or the upper crypt region of the small intestine or colon, respectively (Florian et al., 2001). In addition, GPx2 is upregulated under conditions of inflammation, for example, during colitis (Florian et al., 2010), chronic hepatitis (Suzuki et al., 2013), or in inflamed lung in response to cigarette smoke (Singh et al., 2006). A high GPx2 expression is also detectable in various tumors of epithelial origin. Colorectal adenomas (Mörk et al., 2000), colorectal carcinomas (Murawaki et al., 2008), and moderately differentiated colorectal tumors (Banning et al., 2008a; Florian et al., 2001) show enhanced GPx2 expression in comparison to
9.1 Introduction .................................................................................................. 189 9.2 Dual Role of Factors Regulating GPx2 Expression...................................... 190
9.2.1 Nrf2 ................................................................................................... 190 9.2.2 Wnt .................................................................................................... 192
9.3 Tumor Stage-Specific Functions of GPx2 ................................................... 193 9.3.1 Redox Regulation ............................................................................. 193 9.3.2 Modulation of Proliferation and Apoptosis ...................................... 194 9.3.3 Inhibition of Inflammation ............................................................... 196
9.4 Conclusion .................................................................................................... 197 Acknowledgments .................................................................................................. 197 References .............................................................................................................. 197
nontransformed tissue. Also extraintestinal tumors of epithelial origin, such as squamous cell carcinomas of the skin (Serewko et al., 2002; Walshe et al., 2007), adenocarcinomas of the lung (Wönckhaus et al., 2006), and ductal mammary carcinomas (Naiki-Ito et al., 2007) display an increased GPx2 expression. Furthermore, GPx2 is highly expressed in hepatocellular carcinomas (Suzuki et al., 2013) and prostate cancer (Naiki et al., 2014). Based on this specific expression pattern, which is not observed for any other GPx, it was supposed that GPx2 plays an important role during inflammation and cancer development. Under selenium shortage, GPx2 expression is kept relatively constant while GPx1 levels decline rapidly. This indicates that GPx2 has a higher priority over other selenoproteins, a phenomenon that is also described as the hierarchy of selenoproteins (Brigelius-Flohé, 1999; Brigelius-Flohé et al., 2001; Wingler et al., 1999).
