15-hydroxyprostaglandin dehydrogenase suppresses K-RasV12-dependent tumor formation in Nu/Nu mice

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Oncogenic Ras mutations are early genetic events in colorectal cancer that induce cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) biosynthesis. PGE2, a downstream product of COX-2, promotes cancer progression by modulating proliferation, apoptosis and angiogenesis. 15-hydroxyprostaglandin dehydrogenase (PGDH) degrades PGE2 and is down-regulated in colorectal cancer, suggesting that PGDH plays a role in regulating PGE2 levels and that PGDH over-expression could attenuate Ras-mediated tumorigenesis. Lentiviral transduction was used to express GFP (18.GFP), K-RasV12 (18.K-RasV12), PGDH (18.PGDH) or both K-RasV12 and PGDH (18.K-RasV12.PGDH) in nontumorigenic rat intestinal epithelial (IEC-18) cells. 18.K-RasV12 cells exhibited increased phosphorylation of MAP kinases and CREB, proliferation rates, COX-2 and microsomal prostaglandin E synthase (mPGES)-1 expression and PGE2 and PGI2 levels. 18.PGDH and 18.K-RasV12.PGDH cells had 104-fold increases in PGDH activity with decreased PGE2 and PGI2 levels, COX-2 and mPGES-1 expression and proliferation rates. 18.GFP, 18.PGDH, and 18.K-RasV12.PGDH cells were unable to grow in soft agar media whereas 18.K-RasV12 cells exhibited anchorage-independent cell growth. Xenografts of implanted 18.K-RasV12 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 PGE2 levels. Xenografts of 18.K-RasV12.PGDH cells exhibited delayed (8 wk) tumor formation with negligible COX-2 and mPGES-1 expression and significantly decreased PGE2 levels. 18.K-RasV12.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-RasV12-mediated tumorigenesis in intestinal epithelial cells. © 2007 Wiley-Liss, Inc.

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