Mammalian 2-Cys peroxiredoxin (Prx) enzymes are overexpressed in most cancer tissues, but their specific signaling role in cancer progression is poorly understood. Here we demonstrate that Prx type II (PrxII) plays a tumor-promoting role in colorectal cancer by interacting with a poly(ADP-ribose) polymerase (PARP) tankyrase. PrxII deletion in mice with inactivating mutation of adenomatous polyposis coli (APC) gene reduces intestinal adenomatous polyposis via Axin/β-catenin axis and thereby promotes survival. In human colorectal cancer cells with APC mutations, PrxII depletion consistently reduces the β-catenin levels and the expression of β-catenin target genes. Essentially, PrxII depletion hampers the PARP-dependent Axin1 degradation through tankyrase inactivation. Direct binding of PrxII to tankyrase ARC4/5 domains seems to be crucial for protecting tankyrase from oxidative inactivation. Furthermore, a chemical compound targeting PrxII inhibits the expansion of APC-mutant colorectal cancer cells in vitro and in vivo tumor xenografts. Collectively, this study reveals a redox mechanism for regulating tankyrase activity and implicates PrxII as a targetable antioxidant enzyme in APC-mutation-positive colorectal cancer.
Bibliographical noteFunding Information:
We thank Drs. Chang-Woo Lee and Goo Taeg Oh for sharing plasmids and knockout mice, respectively, and Sue Goo Rhee for valuable comments. This study was supported by grants from the National Research Foundation of Korea (2014R1A2A1A01006934) and from the National R&D Program for Cancer Control (1420280). This study was also supported in part by grants from the National Research Foundation of Korea (2012M3A9C5048709 and 2012R1A5A1048236). D.H.K. was a recipient of a Basic Science Research Program Award from the National Research Foundation of Korea (NRF-2014R1A6A3A04058006). E.-H.J. was supported by the 2016 sabbatical year research grant of the University of Seoul.
© The Author(s) 2017.