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

The effects of the liver tumor promoters phenobarbital, clofibrate, dieldri n, and DDT on transforming growth factor-beta 1 (TGF beta)-induced apoptosi s were studied in FTO-2B hepatoma cells. inhibition of apoptosis by these c ompounds was strongly correlated with a decrease in CPP32-like caspase acti vity. Similar effects were obtained with insulin and dexamethasone. CPP32-l ike activity may thus provide a useful tool for quantiation of apoptosis un der various treatment conditions. Diverse effects on apoptosis-associated c ellular signaling proteins were observed: insulin led to an activation of t he MAP kinases ERK1/2, of PKB/Akt and of NF-kappa B, phenobarbital and clof ibrate enhanced NF-kappa B activity solely, while dexamethasone slightly en hanced NF-kappa B activity and increased the expression of Bcl-x(L). Since inhibition of apoptosis was still detectable if the anti-apoptotic compound s were administered more than 10 h after TGF beta, the diverse primary sign als appear to converge at a presumably late stage of apoptosis, but upstrea m of activation of CPP32 or related caspases.