Retinoic acid inhibits beta-catenin through suppression of Cox-2: a role for truncated adenomatous polyposis coli.
Mutations in adenomatous polyposis coli (APC) underlie the earliest stages of colorectal carcinogenesis. Consequences of APC mutation include stabilization of beta-catenin, dysregulation of cyclooxygenase-2 (COX-2) expression, and loss of retinoic acid production, events with poorly defined interactions. Here we showed that treatment of zebrafish expressing a truncated form of Apc with either retinoic acid or a selective COX-2 inhibitor decreased beta-catenin protein levels and downstream signaling events. Interestingly, the destruction of beta-catenin in apc mutant embryos following Cox-2 inhibition required the presence of truncated Apc. These findings support roles for retinoic acid and Cox-2 in regulating the stability of beta-catenin following Apc loss. Furthermore, truncated Apc appears to retain the ability to target beta-catenin for destruction, but only in the absence of Cox-2 activity. This novel function of truncated Apc may provide a molecular basis for the efficacy of COX-2 inhibitors in the treatment of colon cancer.
Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84112, USA.
Annie L
AL
Eisinger
Lincoln D
LD
Nadauld
Dawne N
DN
Shelton
Stephen M
SM
Prescott
Diana M
DM
Stafforini
David A
DA
Jones
D011125:Adenomatous Polyposis Coli / Q000378:metabolism*; D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D015151:Immunoblotting; D017403:In Situ Hybridization; D009154:Mutation; D012313:RNA / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology*; D015027:Zebrafish; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D051176:beta Catenin; D014212:Tretinoin; D012313:RNA; D051546:Cyclooxygenase 2; D015232:Dinoprostone