4-hydroxynonenal induces apoptosis via caspase-3 activation and cytochrome c release.
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.
Ji
C
C
Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Amarnath
V
V
Pietenpol
J A
JA
Marnett
L J
LJ
D000447:Aldehydes / Q000009:adverse effects*; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000473:pathology; D003432:Cross-Linking Reagents / Q000009:adverse effects*; D003574:Cytochrome c Group / Q000378:metabolism*; D004249:DNA Damage; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2; D006801:Humans; D015227:Lipid Peroxidation; D008928:Mitochondria / Q000201:enzymology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D000447:Aldehydes; D003432:Cross-Linking Reagents; D003574:Cytochrome c Group; D019253:Proto-Oncogene Proteins c-bcl-2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C027576:4-hydroxy-2-nonenal