4-hydroxynonenal induces apoptosis via caspase-3 activation and cytochromec release

We investigated the mechanism by which 4-hydroxynonenal (HNE), a major alde hydic product of lipid peroxidation, induces apoptosis in tumor cells. Trea tment of human colorectal carcinoma (RKO) cells with HNE-induced poly-ADP-r ibose-polymerase (PARP) cleavage and DNA fragmentation in a dose- and time- dependent manner. The induction of PARP cleavage and DNA fragmentation para lleled caspase-2, -3, -8, and -9 activation. Pretreatment of cells with an inhibitor of caspase-3, z-DEVD-fmk, or a broad spectrum caspase inhibitor, z-VAD-fmk, abolished caspase activation and subsequent PARP cleavage. Const itutive expression of high levels of Bcl-2 protected cells from HNE-mediate d apoptosis. In addition, Bcl-2 overexpression inhibited cytochrome c relea se from mitochondria and subsequent caspase-2, -3, and -9 activation. These findings demonstrate that HNE triggers apoptotic cell death through a mito chondrion-dependent pathway involving cytochrome c release and caspase acti vation. Bcl-2 overexpression protected cells from HNE-induced apoptosis thr ough inhibition of cytochrome c release.