
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
Colorectal cancer (CRC) is a cause of the highest cancer mortality in developed countries and is characterized by inactivating mutations of the adenomatous polyposis coli (APC) suppressor gene. APC is a key scaffold protein in the β-catenin destruction complex, which is composed of the axis inhibition protein 1 (Axin1), β-catenin, casein kinase 1 (CK1) and glycogen synthase kinase (GSK)-3β. Axis inhibition protein 1 (Axin1) tumor suppressor is another scaffold protein in the b-catenin destruction complex, but endogenous Axin1 proteins are tightly controlled by tankyrase-dependent degradation in colorectal cancer cells. However, the molecular mechanism regulating tankyrase (TNKS) activity in CRC remains largely unknown. To date, numerous studies have shown that initiation of intestinal tumorigenesis by APC mutations is promoted by the acquired or inherited mutation in the DNA glycosylase enzymes essential for base excision repair of oxidative DNA damage, suggesting the involvement of elevated levels of reactive oxygen species (ROS) in driving the intestinal tumorigenesis driven by APC mutations. Mammalian 2-Cys Prx enzymes are actually the most efficient peroxidases regulating cellular ROS level. These proteins catalyze the reduction of H2O2 to water in the presence of NADPH by coupling with the thioredoxin/thioredoxin reductase system. It has been well established that 2-Cys Prx enzymes have multifaceted roles in cellular ROS detoxification and signal transduction. This study primarily focused on elucidating a molecular mechanism involving TNKS and a thiol peroxidase named PrxII that may be necessary for the survival of CRC cells.
Somatic mutations on oncogenes and tumor suppressors cause intrinsic oxidative stress in cancer cells by amplifying ROS production. ROS has been recognized to serve a double-edged function, where a moderate and transient induction of cellular ROS levels is undoubtedly required for hyper-proliferation of cancer cells due to a second messenger role in growth factor signaling. In contrast, excessive production of ROS can be mutagenic and cytotoxic due to oxidative damage of macromolecules. Kang
TNKS, the sole PARsylating enzyme for regulating the level of Axin proteins, specifically interacts with the glycine residue at position 116 of PrxII through its ankyrin repeat cluster (ARC) 4/5 domains. Endogenous Axin1 proteins are tightly controlled by TNKS-dependent degradation via PARsylation and subsequent ubiquitination in CRC cells. It was shown for the first time that absence of PrxII reduced oncogenic β-catenin in the adenomatous polyps as well as the
In conclusion, the study provided intrinsic mechanistic evidence for a tumor-promoting role specific to PrxII, but not PrxI, beyond its canonical antioxidant role. Specifically, PrxII protected TNKS activity by directing binding to TNKS via ARC4/5 domains in the cytosol and consequently preserved the deregulated β-catenin pathway in APC-mutant CRC cells. Hence, targeting of PrxII may exert specific and broad therapeutic potentials for treating familial adenomatous polyposis (FAP) and
This work was supported by grants from the National Research Foundation of Korea (2014R1A2A1A01006934, 2012M3A9C 5048709 and 2012R1A5A1048236) and National R&D Program for Cancer Control (1420280).
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