In short, COX-2 or 5-LOX deletion and its inhibitors enhanced activity of PTEN and suppressed cell and adenoma progression through PI3K/AKT pathway in colorectal cancer.
To elucidate the involved mechanisms, two colon-relevant metabolites of the polyphenolic and fiber PMD components, urolithin-A (u-A) and sodium butyrate (SB), are tested alone or in combination in vitro (colon cancer cells), and ex vivo in adenoma (AD) and normal mucosa (NM) from Pirc rats. u-A 25 μm plus SB 2.5 mm (USB) causes a significant reduction in COX-2 protein expression compared to untreated controls (about -70% in cancer cell cultures, AD, and NM), and a strong increase in C-CASP-3 expression in cells (about ten times), in AD and NM (+74 and +69%).
However, subset analysis suggested that this lack of response to celecoxib was confined to those patients with 15-PGDH intact tumors who were also using cardioprotective aspirin.<b>Conclusions:</b> The expression of Cox-2 and 15-PGDH in pre-treatment adenomas provides predictive information in patients treated with celecoxib for prevention of colorectal adenomas.<b>Impact:</b> The results of this study show that Cox-2 and 15-PGDH are characteristics of colorectal adenomas that may be used to predict nonsteroidal anti-inflammatory drug chemoprevention efficacy.
COX-2 inhibitors seem to be more effective in preventing recurrence of adenomas; however, there was a trend of an increased risk of recurrence of adenomas observed after discontinuing regular use.
PTGS2 mRNA levels were higher in mild/moderate adenoma tissue compared to morphologically normal tissue from the same individual (P<0.0001) and (P<0.035) and compared to mucosa from healthy individuals (P<0.0039) and (P<0.0027), respectively.
Immunostaining indicated decreased 11β-HSD2 and COX-2 expression in adenoma epithelia, whereas stromal COX-2 expression was intact in Vil-Cre-HSD2(-/-) Apc(min/+) mice.
Clinical trials of COX-2 inhibitors have provided the "proof of principle" that inhibition of this enzyme can prevent the formation of colonic adenomas and potentially carcinomas, however concerns regarding the potential toxicity of these drugs have limited their use as a chemopreventative strategy.
Further, the use of both non-steroidal anti-inflammatory drugs including cyclooxygenase-2 inhibitors is associated with a decreased incidence of adenoma and reduced mortality rate of CRC.
We did not observe the previously reported effects and effect modification in PG-endoperoxide synthase 2 (PTGS2), PGE receptor 2 (PTGER2), or PGE receptor 4 (PTGER4), although we did observe a single nucleotide polymorphism in PTGER2 associated with risk of multiple adenomas.
Several genes including Tiam1, Gastrin, CD44, uPA, Igfbp4, VEGF and Cox-2 that are known to be transcriptionally regulated by activation of the Wnt signaling pathway were found to be expressed at higher levels in the large intestinal adenomas from K-rasVal12/Cre/ApcMin/+ mice compared with those from controls, although other Wnt signaling pathway target genes remained unchanged.
Strong COX-2 expression predominated in adenomas larger than 10 mm (84/129 vs 44/90; p=0.02) and in adenomas showing high-grade dysplasia (22/29 vs 104/188; p=0.04).
Furthermore, pharmacologic inhibition or gene silencing of 11betaHSD2 inhibited COX-2-mediated PGE2 production in tumors and prevented adenoma formation, tumor growth, and metastasis in mice.
In this study, we show that the adenoma prevention activity of the COX-2 inhibitor celecoxib requires the concomitant presence of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) tumor suppressor gene, and that loss of 15-PGDH expression imparts resistance to celecoxib's anti-tumor effects.
The data from our pilot study suggest that allelic variants of the COX-2 gene significantly influence the risk of adenoma development in the African American population.
Third, using the Apc Min/+ mice model, we demonstrated that inhibition of the CD44v6 expression reduces the signaling through a hyaluronan/CD44v6-pErbB2-Cox-2 interaction pathway and reduced adenoma number and growth.
The data from our pilot study suggest that allelic variants of the COX-2 gene significantly influence the risk of adenoma development in the African American population.
Adjusted relative risks and 95% confidence intervals (95% CI) were calculated to test the association between genetic variation at six COX-2 single-nucleotide polymorphisms and adenoma occurrence and interaction with aspirin treatment.
HuR and COX-2 protein expression were studied by immunohistochemistry of normal colon mucosa (N=20), adenomas (N=112), carcinomas (N=9) from patients with FAP, and 141 sporadic colorectal adenocarcinomas (Dukes B and C).