Mutations in adenomatous polyposis coli (APC) underlie the earliest stages of colorectal carcinogenesis. Consequences of APC mutation include stabilization of -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 -catenin protein levels and downstream signaling events. Interestingly, the destruction of -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 -catenin following Apc loss. Furthermore, truncated Apc appears to retain the ability to target -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.Retinoids are important regulators of differentiation and cell proliferation. Induction of differentiation by retinoic acid has been observed in endothelial, melanoma, neuroblastoma, and lung cancer cells (1). Retinoic acid has been shown to inhibit the growth of breast cancer cell lines and to reduce the average number and incidence of tumors in an animal model of breast cancer (2-4). The anti-tumor potential of retinoids has been demonstrated by their ability to inhibit the growth of several human cancers, including colon and prostate cancer and melanoma (5-7). Retinoic acid mediates its effects by binding to its receptors, retinoic acid receptor (RAR), 4 or retinoid X receptor (RXR), followed by heterodimerization and recognition of RAR element-containing promoters. In cells that express the transcription factor AP-1, retinoic acid regulates cell growth by inhibiting the formation of AP-1 complexes capable of DNA binding (8 -10). In SW480 colon cancer cells, retinoic acid associates with its receptor RAR, and the complex sequesters -catenin from the TCF transcription factor, thus preventing transcription of -catenin/TCF target genes (11). In addition, RXR agonists induce degradation of -catenin through a proteasome-dependent process (12).-Catenin is a multifunctional protein that transduces Wnt signals, mediates cell-cell adherens junctions through its interaction with E-cadherin, and stimulates cell proliferation. -Catenin is regulated by, and forms part of, a multiprotein complex that also includes APC, axin, glycogen synthase kinase-3 (GSK-3), and casein kinase 1 (13-19). Under basal conditions, -catenin associates with APC and axin, and it becomes phosphorylated by casein kinase 1 and GSK-3 (20, 21). Phosphorylation of -catenin marks the protein for ubiquitination and subsequent degradation by the proteasome (22-25). Mutations in members of the -catenin complex can compromise its integrity and ability to destabilize -catenin. For example, impaired function of APC, which is observed ...