4-hydroxynonenal induces apoptosis via caspase-3 activation and cytochrome c release.

Ji C, Amarnath V, Pietenpol JA, Marnett LJ
Chem Res Toxicol. 2001 14 (8): 1090-6

PMID: 11511183 · DOI:10.1021/tx000186f

We investigated the mechanism by which 4-hydroxynonenal (HNE), a major aldehydic product of lipid peroxidation, induces apoptosis in tumor cells. Treatment of human colorectal carcinoma (RKO) cells with HNE-induced poly-ADP-ribose-polymerase (PARP) cleavage and DNA fragmentation in a dose- and time-dependent manner. The induction of PARP cleavage and DNA fragmentation paralleled 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. Constitutive expression of high levels of Bcl-2 protected cells from HNE-mediated apoptosis. In addition, Bcl-2 overexpression inhibited cytochrome c release from mitochondria and subsequent caspase-2, -3, and -9 activation. These findings demonstrate that HNE triggers apoptotic cell death through a mitochondrion-dependent pathway involving cytochrome c release and caspase activation. Bcl-2 overexpression protected cells from HNE-induced apoptosis through inhibition of cytochrome c release.

MeSH Terms (16)

Aldehydes Apoptosis Caspase 3 Caspases Colorectal Neoplasms Cross-Linking Reagents Cytochrome c Group DNA Damage Enzyme Induction Gene Expression Regulation, Neoplastic Genes, bcl-2 Humans Lipid Peroxidation Mitochondria Proto-Oncogene Proteins c-bcl-2 Tumor Cells, Cultured

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