Interaction of tankyrase and peroxiredoxin II is indispensable for the survival of colorectal cancer cells

Dong Hoon Kang, Doo Jae Lee, Sunmi Lee, So-Young Lee, Yukyung Jun, Yerin Kim, Youngeun Kim, Ju-Seog Lee, Dae-Kee Lee, Sanghyuk Lee, Eek-Hoon Jho, Dae-Yeul Yu and Sang Won Kang ()
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Dong Hoon Kang: Ewha Womans University
Doo Jae Lee: Ewha Womans University
Sunmi Lee: Ewha Womans University
So-Young Lee: Ewha Womans University
Yukyung Jun: Ewha Womans University
Yerin Kim: Ewha Womans University
Youngeun Kim: University of Seoul
Ju-Seog Lee: UT MD Anderson Cancer Center
Dae-Kee Lee: Ewha Womans University
Sanghyuk Lee: Ewha Womans University
Eek-Hoon Jho: University of Seoul
Dae-Yeul Yu: Aging Research Center, KRIBB
Sang Won Kang: Ewha Womans University

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00054-0

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