Abstract
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.
Highlights
N-(4-hydroxyphenyl)retinamide (4HPR), a chemopreventive and chemotherapeutic retinoid, induces apoptosis in various types of cells
We have observed that 4HPR effectively induces apoptosis in hepatoma cells, the susceptibility to 4HPR-induced apoptosis differs in a cell-specific manner. 4HPR decreases levels of the cytochrome c oxidase subunit III (CO III) transcript, which is accompanied by a decrease in cytochrome c oxidase activity during apoptosis
The cells displayed disintegrated nuclei and nonrandom DNA fragmentation, as assessed by agarose gel electrophoresis of genomic DNA (Fig. 1B). These results suggest that 4HPR-triggered cell death is independent of p53-induced apoptosis and that cells with wild-type p53 are resistant to 4HPR
Summary
N-(4-hydroxyphenyl)retinamide (4HPR), a chemopreventive and chemotherapeutic retinoid, induces apoptosis in various types of cells. We further observed that 4HPR down-regulates cytochrome c oxidase subunit III (CO III) transcript levels through destabilization of its mRNA and 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 (⌬⌿m) without altering CO III transcription. 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 ⌬⌿m disruption and that ligands of ANT may be capable of modulating 4HPR-induced oxidative stress and apoptosis. The aim of this study was to elucidate the mechanism whereby the CO III transcript is decreased and to examine whether the 4HPR-induced oxidative stress and apoptosis is modulated
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