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

Artikel i vetenskaplig tidskrift
Författare Lubna M Mehdawi
Shakti Ranjan Satapathy
Annika Gustafsson Asting
Kent Lundholm
Maria Alvarado-Kristensson
Anita Sjölander
Publicerad i Oncotarget
ISSN 1949-2553
Publiceringsår 2017
Publicerad vid Institutionen för kliniska vetenskaper, sektionen för kirurgi och kirurgisk gastroforskning, Avdelningen för kirurgi
Språk en
Länkar dx.doi.org/10.18632/oncotarget.1659...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Gastroenterologi, Cancer och onkologi, Cell- och molekylärbiologi

Sammanfattning

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.

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