A potential anti-tumor effect of leukotriene C₄ through the induction of 15-hydroxyprostaglandin dehydrogenase expression in colon cancer cells

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.