Survival of APC-mutant colorectal cancer cells requires interaction between tankyrase and a thiol peroxidase, peroxiredoxin II

BMB Reports

Dong Hoon Kang^1,2¹  Joanna H.S. Lee^1² 

[1] Department of Life Sciences, Ewha Womans University, Seoul 03760, Korea^1;Research Center for Cell Homeostasis, Ewha Womans University, Seoul 03760, Korea^2

关键词: Axin;   

DOI  :  10.5483/BMBRep.2017.50.8.120

学科分类：生物化学/生物物理

来源: Korean Society for Biochemistry and Molecular Biology

【 摘 要 】

Overexpression of mammalian 2-Cys peroxiredoxin (Prx) enzymes is observed in most cancer tissues. Nevertheless, their specific roles in colorectal cancer (CRC) progression has yet to be fully elucidated. Here, a novel molecular mechanism by which PrxII/Tankyrase (TNKS) interaction mediates survival of adenomatous polyposis coli (APC)-mutant CRC cells was explored. In mice with an inactivating APC mutation, a model of spontaneous intestinal tumorigenesis, deletion of PrxII reduced intestinal adenomatous polyposis and thereby increased survival. In APC-mutant human CRC cells, PrxII depletion hindered PARP-dependent Axin1 degradation through TNKS inactivation. H2O2-sensitive Cys residues in the zinc-binding domain of TNKS1 was found to be crucial for PARsylation activity. Mechanistically, direct binding of PrxII to ARC4/5 domains of TNKS conferred vital redox protection against oxidative inactivation. As a proof-of-concept experiment, a chemical compound targeting PrxII inhibited the growth of tumors xenografted with APC-mutation-positive CRC cells. Collectively, the results provide evidence revealing a novel redox mechanism for regulating TNKS activity such that physical interaction between PrxII and TNKS promoted survival of APC-mutant colorectal cancer cells by PrxII-dependent antioxidant shielding.

【 授权许可】

Unknown