A potential anti-tumor effect of leukotriene C4 through the induction of 15-hydroxyprostaglandin dehydrogenase expression in colon cancer cells
(2017) In Oncotarget 8(21). p.35033-35047- 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... (More)
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.
(Less)
- author
- Mehdawi, Lubna M. LU ; Satapathy, Shakti Ranjan LU ; Hagenbjork-Gustafsson, Annika ; Lundholm, Kent ; Alvarado-Kristensson, Maria LU and Sjölander, Anita LU
- organization
- publishing date
- 2017
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- 15-PGDH, Anti-tumor, Colon cancer, CysLTR2, LTC4 signaling
- in
- Oncotarget
- volume
- 8
- issue
- 21
- pages
- 15 pages
- publisher
- Impact Journals
- external identifiers
-
- pmid:28402256
- wos:000402051700090
- scopus:85019845903
- ISSN
- 1949-2553
- DOI
- 10.18632/oncotarget.16591
- language
- English
- LU publication?
- yes
- id
- d402e258-8e94-4096-83f8-08b796dda59e
- date added to LUP
- 2017-06-16 13:26:20
- date last changed
- 2024-08-04 23:32:26
@article{d402e258-8e94-4096-83f8-08b796dda59e, abstract = {{<p>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 E<sub>2</sub> (PGE<sub>2</sub>), is often up-regulated in CRC and in other types of cancer. PGE<sub>2</sub> induces angiogenesis and tumor cell survival, proliferation and migration. The tumor suppressor 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme in PGE<sub>2</sub> catabolism, converting it into its inactive metabolite 15-keto- PGE<sub>2</sub>, and is often down-regulated in cancer. Interestingly, CRC patients expressing high levels of the cysteinyl leukotriene 2 (CysLT<sub>2</sub>) 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 LTC<sub>4</sub>, a CysLT<sub>2</sub> ligand, in colon cancer cells at both the mRNA and protein levels, which could be reduced by a CysLT<sub>2</sub> antagonist or a JNK inhibitor. LTC<sub>4</sub> induced 15-PGDH promoter activity via JNK/AP-1 phosphorylation. Furthermore, we also observed that LTC<sub>4</sub>, via the CysLT<sub>2</sub>/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 CysLT<sub>2</sub> signaling promotes the differentiation of colon cancer cells, indicating an anti-tumor effect of CysLT<sub>2</sub> signaling.</p>}}, author = {{Mehdawi, Lubna M. and Satapathy, Shakti Ranjan and Hagenbjork-Gustafsson, Annika and Lundholm, Kent and Alvarado-Kristensson, Maria and Sjölander, Anita}}, issn = {{1949-2553}}, keywords = {{15-PGDH; Anti-tumor; Colon cancer; CysLTR2; LTC4 signaling}}, language = {{eng}}, number = {{21}}, pages = {{35033--35047}}, publisher = {{Impact Journals}}, series = {{Oncotarget}}, title = {{A potential anti-tumor effect of leukotriene C<sub>4</sub> through the induction of 15-hydroxyprostaglandin dehydrogenase expression in colon cancer cells}}, url = {{http://dx.doi.org/10.18632/oncotarget.16591}}, doi = {{10.18632/oncotarget.16591}}, volume = {{8}}, year = {{2017}}, }