Abstract
The activation of the Wnt/β-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 β-catenin, reduce β-catenin mRNA and protein levels, and suppress the transcriptional activity of β-catenin. This review describes the relationship between the Wnt/β-catenin signaling cascade and the activation of PKG through PDE inhibition and elevation of intracellular cGMP levels.
Highlights
Colorectal cancer (CRC) is the third most common type of cancer among men and women in the United States
It was shown that certain PDEs (PDE5, and PDE10) were expressed in high levels in tumor cells when compared to normal cells of the same tissue origin and that when these phosphodiesterases were inhibited through either pharmacological mechanisms or through genetic silencing, cyclic nucleotide levels were increased leading to activation of protein kinases, PKG and PKA
non-steroidal anti-inflammatory drugs (NSAIDs) are known to be effective for the treatment of patients with familial adenomatous polyposis (FAP) but are not FDA approved for such a use due to potentially fatal side effects relating to their cyclooxygenase inhibitory activity and suppression of physiologically important prostaglandins
Summary
Colorectal cancer (CRC) is the third most common type of cancer among men and women in the United States. CLC number: R458, Document code: A The authors reported no conflict of interests. Phosphorylated Dvl associates with Axin, inducing dissociation of the βcatenin destruction complex. Once in the nucleus βcatenin binds to T cell factor/lymphoid-enhancer factor (Tcf/Lef) transcription factors and activates the transcription of several target genes, which can include cMyc, cyclin D1, gastrin, and ITF-2 (Fig. 1)[9,10,11,12,13,14]
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