| Abstract | Oncogenic Ras mutations are early genetic events in colorectal cancer that induce cyclooxygenase (COX)-2 expression and prostaglandin E(2) (PGE(2)) biosynthesis. PGE(2), a downstream product of COX-2, promotes cancer progression by modulating proliferation, apoptosis and angiogenesis. 15-hydroxyprostaglandin dehydrogenase (PGDH) degrades PGE(2) and is down-regulated in colorectal cancer, suggesting that PGDH plays a role in regulating PGE(2) levels and that PGDH over-expression could attenuate Ras-mediated tumorigenesis. Lentiviral transduction was used to express GFP (18.GFP), K-Ras(V12) (18.K-Ras(V12)), PGDH (18.PGDH) or both K-Ras(V12) and PGDH (18.K-Ras(V12).PGDH) in nontumorigenic rat intestinal epithelial (IEC-18) cells. 18.K-Ras(V12) cells exhibited increased phosphorylation of MAP kinases and CREB, proliferation rates, COX-2 and microsomal prostaglandin E synthase (mPGES)-1 expression and PGE(2) and PGI(2) levels. 18.PGDH and 18.K-Ras(V12).PGDH cells had 10(4)-fold increases in PGDH activity with decreased PGE(2) and PGI(2) levels, COX-2 and mPGES-1 expression and proliferation rates. 18.GFP, 18.PGDH, and 18.K-Ras(V12).PGDH cells were unable to grow in soft agar media whereas 18.K-Ras(V12) cells exhibited anchorage-independent cell growth. Xenografts of implanted 18.K-Ras(V12) cells in nu/nu mice produced rapid (2 wk) tumors with uniform antibody staining for COX-2 and mPGES-1 throughout the tumor and elevated PGE(2) levels. Xenografts of 18.K-Ras(V12).PGDH cells exhibited delayed (8 wk) tumor formation with negligible COX-2 and mPGES-1 expression and significantly decreased PGE(2) levels. 18.K-Ras(V12).PGDH tumors had decreased staining of the proliferative marker, Ki-67, and a significant increase in apoptosis in the central region of the tumor. Based on these data, we conclude that PGDH expression suppresses K-Ras(V12)-mediated tumorigenesis in intestinal epithelial cells. |
| Authors | Hung Pham, Guido Eibl, Romina Vincenti, Benny Chong, Hsin-Hsiung Tai, Lee W Slice
(Affiliation: Department of Medicine, Division of Digestive Diseases, University of California, Los Angeles, California, USA.)
|
| Journal | Molecular carcinogenesis
(Mol Carcinog)
Vol. 47
Issue 6
Pg. 466-77
(Jun 2008)
ISSN: 1098-2744 United States |
| PMID | 18058808
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
| Copyright | (c) 2007 Wiley-Liss, Inc. |
| Chemical References |
- Cyclic AMP Response Element-Binding Protein
- DNA Primers
- Prostaglandins
- Hydroxyprostaglandin Dehydrogenases
- 15-hydroxyprostaglandin dehydrogenase
- Mitogen-Activated Protein Kinases
|
| Topics |
- Animals
- Base Sequence
- Cell Division
- Cyclic AMP Response Element-Binding Protein
(metabolism)
- DNA Primers
- Genes, ras
- Hydroxyprostaglandin Dehydrogenases
(metabolism)
- Immunohistochemistry
- In Situ Nick-End Labeling
- Mice
- Mice, Nude
- Mitogen-Activated Protein Kinases
(metabolism)
- Neoplasms, Experimental
(enzymology, metabolism, pathology, prevention & control)
- Phosphorylation
- Prostaglandins
(metabolism)
- Rats
- Reverse Transcriptase Polymerase Chain Reaction
|
