Cytochrome c oxidase subunit III: a molecular marker for N-(4-hydroxyphenyl)retinamise-induced oxidative stress in hepatoma cells.
N-(4-hydroxyphenyl)retinamide (4HPR), a chemopreventive and chemotherapeutic retinoid, induces apoptosis in various types of cells. Currently, oxidative mitochondrial damage is thought to cause 4HPR-induced apoptosis, although the exact mechanism has not yet been clarified. 4HPR effectively induces apoptosis in hepatoma cells although the susceptibility differs in a cell-specific manner. Hep-3B and PLC/PRF/5 cells were more susceptible to 4HPR than were Hep-G2 and SK-HEP-1 cells, and the resistance to 4HPR seems to be related to growth inhibition (G(1) arrest). We further observed that 4HPR specifically down-regulates cytochrome c oxidase subunit III (CO III) transcript levels through destabilization of its mRNA and thus decreases the activity of cytochrome c oxidase (complex IV). To explore the mechanism whereby the CO III transcript was decreased by 4HPR, we used adenine nucleotide translocator (ANT) ligands, which modulate mitochondrial transmembrane potential (deltapsi(m)) without altering CO III transcription. Intriguingly, bongkrekic acid, a specific ANT inhibitor, enhanced 4HPR-induced deltapsi(m) disruption, which in turn decreased the level of CO III transcripts, which was accompanied by increases in the generation of reactive oxygen species and in apoptosis. In contrast, atractyloside, an activator of ANT, inhibited those 4HPR-induced effects. Taken together, these results indicate that down-regulation of CO III, a molecular marker of oxidative stress, may result from upstream deltapsi(m) disruption and that ligands of ANT may be capable of modulating 4HPR-induced oxidative stress and apoptosis.
You
Kyung-Ran
KR
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute for Molecular Biology and Genetics, Chonbuk National University Medical School and Hospital, Chonju, Chonbuk 561-712, Republic of Korea.
Wen
Jing
J
Lee
Soo-Taek
ST
Kim
Dae-Ghon
DG
D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D003576:Electron Transport Complex IV / Q000378:metabolism*; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D014407:Tumor Cells, Cultured
D017313:Fenretinide; D003576:Electron Transport Complex IV