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

Mehdawi, Lubna M. LU ; Satapathy, Shakti Ranjan LU ; Hagenbjork-Gustafsson, Annika; Lundholm, Kent; Alvarado-Kristensson, Maria LU and Sjölander, Anita LU (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.

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author
organization
publishing date
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, LLC
external identifiers
  • scopus:85019845903
  • wos:000402051700090
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
2018-01-07 12:08:14
@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},
  keyword      = {15-PGDH,Anti-tumor,Colon cancer,CysLTR2,LTC4 signaling},
  language     = {eng},
  number       = {21},
  pages        = {35033--35047},
  publisher    = {Impact Journals, LLC},
  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},
  volume       = {8},
  year         = {2017},
}