NITRIC-OXIDE SUPPRESSION OF APOPTOSIS OCCURS IN ASSOCIATION WITH AN INHIBITION OF BCL-2 CLEAVAGE AND CYTOCHROME-C RELEASE

It is now known that caspase-3-like protease activation can promote Bc I-2 cleavage and mitochondrial cytochrome c release and that these eve nts can lead to further downstream caspase activation. NO has been pro posed as a potent, endogenous inhibitor of caspase-3-like protease act ivity. Experiments were carried out to determine whether NO could inte rrupt Bcl-2 cleavage or cytochrome c release by the inhibition of casp ase activity linking these events. NO inhibited the capacity of purifi ed caspase-3 to cleave recombinant Bcl-2. Both Bcl-2 cleavage and cyto chrome c release were inhibited in tumor necrosis factor alpha- and ac tinomycin D-treated MCF-7 cells exposed to NO donors. The NO-mediated inhibition of Bcl-2 cleavage and cytochrome c release occurred in asso ciation with an inhibition of apoptosis and caspase-3-like activation. Thus, NO suppresses a key step in the positive feedback amplification of apoptotic signaling by preventing Bcl-2 cleavage and cytochrome c release.