Survival of APC-mutant colorectal cancer cells requires interaction between tankyrase and a thiol peroxidase, peroxiredoxin II
- 주제(키워드) Axin , Colorectal cancer , Peroxiredoxin , Tankyrase , β-catenin
- 등재 SCIE, SCOPUS, KCI등재
- 발행기관 The Biochemical Society of the Republic of Korea
- 발행년도 2017
- URI http://www.dcollection.net/handler/ewha/000000155950
- 본문언어 영어
- Published As http://dx.doi.org/10.5483/BMBRep.2017.50.8.120
초록/요약
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 zincbinding 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. © 2017 by the The Korean Society for Biochemistry and Molecular Biology.
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