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  • Title: Insulin and dexamethasone inhibit TGF-beta-induced apoptosis of hepatoma cells upstream of the caspase activation cascade.
    Author: Wanke I, Schwarz M, Buchmann A.
    Journal: Toxicology; 2004 Nov 15; 204(2-3):141-54. PubMed ID: 15388240.
    Abstract:
    Insulin and dexamethasone are potent inhibitors of apoptosis induced by transforming growth factor-beta1 (TGF-beta) in hepatoma cells. Using FTO-2B rat hepatoma cells, we determined whether the anti-apoptotic effects of these agents result from interference within or upstream of the TGF-beta-induced caspase cascade. Activation of different initiator and effector caspases, Bax and Bcl-xL expression, mitochondrial cytochrome c release and activation of PKB/Akt were analyzed by use of synthetic caspase substrates and Western blotting, respectively. TGF-beta-induced apoptosis was characterized by release of cytochrome c from mitochondria and activation of caspases-3, -7, -8 and -9. These effects were observable as early as 8-12 h after start of treatment and increased with time of observation. Inhibition of TGF-beta-induced apoptosis by insulin and dexamethasone was paralleled by a strong reduction of caspase-3-like activity. Caspase-8 activation was almost completely suppressed by these agents, and caspase-9 activity was decreased to levels within or slightly above unstimulated control cells. In addition, cytochrome c release from mitochondria was efficiently repressed, which was associated with upregulation of Bcl-xL by dexamethasone and activation of PKB/Akt by insulin. Thus, both anti-apoptotic compounds exert their inhibitory effects through modulation of anti-apoptotic signalling pathways involved in regulation of cytochrome c release and activation of the caspase machinery.
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