Apoptosis, mitosis and cyclophilin-40 expression in regressing peroxisome proliferator-induced adenomas

Chronic exposure to peroxisome proliferators (PP), including certain indust rial and pharmaceutical chemicals, causes liver cancer in rodents. Continuo us exposure to pr is needed for tumor development since the frequency of he patocellular neoplasms is decreased in animals returned to control diet. To determine cellular and molecular events responsible for enhanced growth in PR-induced liver tumors, me evaluated the relationships of WY-14,643 level s, apoptosis, mitosis and cyclophilin-40 (Cyp-40) expression in regressing tumors induced by WY-14,643, a potent PP, Male F344 rats were fed WY-14,643 (0.1%) in the diet for 43 weeks and then switched to control diet for 2, 3 , 5 or 36 days, Mean serum and hepatic concentrations of WY-14,643 were dec reased as early as 2 days following removal of WY-14,643 as compared with r ats continuously fed WY-14,643, Adenomas from rats maintained on WY-14,643 markedly compressed surrounding parenchyma, Evidence of adenoma regression was observed by 3 days of WY-14,643 withdrawal and was characterized by los s of compression, Decreased compression corresponded to increases in the ap optotic index and decreases in the mitotic index in regressing adenomas at 2, 3, and 5 days following the switch to control diet. Cyclophilins are mul ti-functional receptor proteins involved in numerous signal transduction pa thways, including those mediated by cyclosporin, a liver tumor promoter in rats, Cyp-40 expression was markedly increased in adenomas from continuousl y exposed rats, but expression returned to levels similar to surrounding pa renchyma in adenomas after 5 days of WY-14,643 withdrawal. Taken together, these results indicate that WY-14,643-induced adenomas regress rapidly foll owing withdrawal of the PP in association with declining liver WY-14,643 le vels, suggesting that peroxisome proliferator-activated receptor alpha may mediate PP-induced alterations in mitogenic and/or apoptotic regulation in growing tumors, in conjunction with alterations in Cyp-40 signal transducti on.