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Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Cyclooxygenase-2, which plays a key role in the biosynthesis of prostaglandin E2 (PGE2), is often up-regulated in CRC and in other types of cancer. PGE2 induces angiogenesis and tumor cell survival, proliferation and migration. The tumor suppressor 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme in PGE2 catabolism, converting it into its inactive metabolite 15-keto-PGE2, and is often down-regulated in cancer. Interestingly, CRC patients expressing high levels of the cysteinyl leukotriene 2 (CysLT2) receptor have a good prognosis; therefore, we investigated a potential link between CysLT2 signaling and the tumor suppressor 15-PGDH in colon cancer cells.We observed a significant up-regulation of 15-PGDH after treatment with LTC4, a CysLT2 ligand, in colon cancer cells at both the mRNA and protein levels, which could be reduced by a CysLT2 antagonist or a JNK inhibitor. LTC4 induced 15-PGDH promoter activity via JNK/AP-1 phosphorylation. Furthermore, we also observed that LTC4, via the CysLT2/JNK signaling pathway, increased the expression of the differentiation markers sucrase-isomaltase and mucin-2 in colon cancer cells and that down-regulation of 15-PGDH totally abolished the observed increase in these markers.In conclusion, the restoration of 15-PGDH expression through CysLT2 signaling promotes the differentiation of colon cancer cells, indicating an anti-tumor effect of CysLT2 signaling.
Highlights
Colorectal cancer (CRC) is considered a major health problem worldwide [1]
15-hydroxyprostaglandin dehydrogenase (15-PGDH) regulates the level of prostaglandin E2 (PGE2) produced through COX-2 and is a tumor suppressor frequently down-regulated in cancers [17, 20]
We investigated the mRNA levels of COX-2, 15-PGDH, and the cysteinyl leukotriene 2 (CysLT2) receptor in 23 colon cancer patients at different stages of the disease and compared the gene expression in normal mucosa and tumor tissues in matched pairs for each patient (Figure 1)
Summary
Colorectal cancer (CRC) is considered a major health problem worldwide [1]. It is the third most common cancer and the third most common cause of cancer-related deaths in both sexes [2]. Eicosanoids are biologically active lipophilic molecules derived from arachidonic acid (AA) that play an essential role in many physiological processes, such as inflammation [5] These compounds are precursors to many different types of pro-inflammatory lipid mediators, such as leukotrienes (LTs) and prostaglandins (PGs), which are www.impactjournals.com/oncotarget important regulators of the tumor microenvironment [5,6]. Gustafsson et al showed that indomethacin, an NSAID, up-regulates 15-PGDH and at least partly decreases the expression of COX-2 in HCA-7 colon cancer cells [19] Taken together, these data indicate that the levels of the pro-tumorigenic PGE2 are increased in CRC, which was previously attributed to the increased production via COX-2 up-regulation but more recently has been attributed to decreased catabolism, reflecting the down-regulation of 15-PGDH. We investigated the potential association between CysLT2 signaling and 15PGDH expression in the pathogenesis of CRC
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