Inhibition of transforming growth factor beta1-induced hepatoma cell apoptosis by liver tumor promoters: characterization of primary signaling events and effects on CPP32-like caspase activity

The effects of the liver tumor promoters phenobarbital, clofibrate, dieldrin, and DDT on transforming growth factor-beta 1 (TGF beta)-induced apoptosis were studied in FTO-2B hepatoma cells. inhibition of apoptosis by these compounds was strongly correlated with a decrease in CPP32-like caspase activity. Similar effects were obtained with insulin and dexamethasone. CPP32-like activity may thus provide a useful tool for quantiation of apoptosis under various treatment conditions. Diverse effects on apoptosis-associated cellular signaling proteins were observed: insulin led to an activation of the MAP kinases ERK1/2, of PKB/Akt and of NF-kappa B, phenobarbital and clofibrate enhanced NF-kappa B activity solely, while dexamethasone slightly enhanced NF-kappa B activity and increased the expression of Bcl-x(L). Since inhibition of apoptosis was still detectable if the anti-apoptotic compounds were administered more than 10 h after TGF beta, the diverse primary signals appear to converge at a presumably late stage of apoptosis, but upstream of activation of CPP32 or related caspases.