Inhibition of beta-catenin translocation in rodent colorectal tumors: a novel explanation for the protective effect of nonsteroidal antiinflammatory drugs in colorectal cancer.
In a rodent colorectal cancer model, nonsteroidal antiinflammatory drugs reduce tumor mass by increasing the rate of tumor cell apoptosis and decreasing proliferation. We have examined beta-catenin as a potential target for these agents in colorectal cancer. Carcinogen-treated rats were treated for 23 weeks with a range of nonsteroidal antiinflammatory drugs. Control animals received vehicle alone. Intracellular beta-catenin was examined using immunohistochemistry. In tumors from untreated animals, staining was seen in the cytoplasm and nucleus (median 24% of nuclei). The frequency of nuclear beta-catenin staining correlated directly with the volume of tumor and inversely with the rate of apoptosis. In tumors from treatment groups, the cytoplasmic staining for beta-catenin was unchanged; however, nuclear staining was absent except in the celecoxib group, where it was reduced to a median of 14%. Colorectal tumors from animals treated with NSAIDs show reduced levels of nuclear beta-catenin immunoreactivity.
Brown
W A
WA
Monash University Department of Surgery, Alfred Hospital, Melbourne, Australia.
Skinner
S A
SA
Vogiagis
D
D
O'Brien
P E
PE
D019813:1,2-Dimethylhydrazine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D015820:Cadherins / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D015534:Trans-Activators; D051176:beta Catenin
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015820:Cadherins; D002273:Carcinogens; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D019813:1,2-Dimethylhydrazine