TY - JOUR
T1 - Repression of prostaglandin dehydrogenase by epidermal growth factor and snail increases prostaglandin E2 and promotes cancer progression
AU - Mann, Jason R.
AU - Backlund, Michael G.
AU - Buchanan, F. Gregory
AU - Daikoku, Taki
AU - Holla, Vijaykumar R.
AU - Rosenberg, Daniel W.
AU - Dey, Sudhansu K.
AU - DuBois, Raymond N.
PY - 2006/7/1
Y1 - 2006/7/1
N2 - Prostaglandin E2 (PGE2), a proinflammatory bioactive lipid, promotes cancer progression by modulating proliferation, apoptosis, and angiogenesis. PGE2 is a downstream product of cyclooxygenase (COX) and is biochemically inactivated by prostaglandin dehydrogenase (PGDH). In the present study, we investigated the mechanisms by which PGDH is down-regulated in cancer. We show that epidermal growth factor (EGF) represses PGDH expression in colorectal cancer cells. EGF receptor (EGFR) signaling induces Snail, which binds conserved E-box elements in the PGDH promoter to repress transcription. Induction of PGE2 catabolism through inhibition of EGFR signaling blocks cancer growth in vivo. In human colon cancers, elevated Snail expression correlates well with down-regulation of PGDH. These data indicate that PGDH may serve a tumor suppressor function in colorectal cancer and provide a possible COX-2-independent way to target PGE2 to inhibit cancer progression.
AB - Prostaglandin E2 (PGE2), a proinflammatory bioactive lipid, promotes cancer progression by modulating proliferation, apoptosis, and angiogenesis. PGE2 is a downstream product of cyclooxygenase (COX) and is biochemically inactivated by prostaglandin dehydrogenase (PGDH). In the present study, we investigated the mechanisms by which PGDH is down-regulated in cancer. We show that epidermal growth factor (EGF) represses PGDH expression in colorectal cancer cells. EGF receptor (EGFR) signaling induces Snail, which binds conserved E-box elements in the PGDH promoter to repress transcription. Induction of PGE2 catabolism through inhibition of EGFR signaling blocks cancer growth in vivo. In human colon cancers, elevated Snail expression correlates well with down-regulation of PGDH. These data indicate that PGDH may serve a tumor suppressor function in colorectal cancer and provide a possible COX-2-independent way to target PGE2 to inhibit cancer progression.
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UR - http://www.scopus.com/inward/citedby.url?scp=33746173092&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-06-1787
DO - 10.1158/0008-5472.CAN-06-1787
M3 - Article
C2 - 16818638
AN - SCOPUS:33746173092
SN - 0008-5472
VL - 66
SP - 6649
EP - 6656
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -