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Kevin Lee,Gary A Piazza.Journal of Biomedical Research,2017,31(3):189-196
The interaction between the Wnt/-catenin signaling cascade and PKG activation in cancer
Received:October 25, 2016  
DOI10.7555/JBR.31.20160133
KeywordsWnt, -catenin, PKG, cGMP, PDE, NSAID, colon cancer, breast cancer
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Kevin Lee Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604-1405, USA
Gary A Piazza Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604-1405, USA
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Abstract
      The activation of the Wnt/-catenin signaling cascade has been well studied and documented in colorectal cancer (CRC). The long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce the incidence and risk of death from CRC in numerous epidemiological studies. The NSAID sulindac has also been reported to cause regression of precancerous adenomas in individuals with familial adenomatous polyposis who are at high risk of developing CRC. The mechanism responsible for cancer chemopreventive activity of NSAIDs is not well understood but may be unrelated to their cyclooxygenase inhibitory activity. Emerging evidence suggests that sulindac inhibits the growth of colon tumor cells by suppressing the activity of certain phosphodiesterase isozymes to activate cGMP-dependent protein kinase, PKG, through the elevation of the second messenger cyclic guanosine monophosphote, cGMP. PKG activation has been shown to inhibit the nuclear translocation of -catenin, reduce - catenin mRNA and protein levels, and suppress the transcriptional activity of -catenin. This review describes the relationship between the Wnt/-catenin signaling cascade and the activation of PKG through PDE inhibition and elevation of intracellular cGMP levels.
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