Chloramphenicol-induced mitochondrial stress increases p21 expression and prevents cell apoptosis through a p21-dependent pathway.
Pretreatment of HepG2 and H1299 cells with chloramphenicol rendered the cells resistant to mitomycin-induced apoptosis. Both mitomycin-induced caspase 3 activity and PARP activation were also inhibited. The mitochondrial DNA-encoded Cox I protein, but not nuclear-encoded proteins, was down-regulated in chloramphenicol-treated cells. Cellular levels of the p21(waf1/cip1) protein and p21(waf1/cip1) mRNA were increased through a p53-independent pathway, possibly because of the stabilization of p21(waf1/cip1) mRNA in chloramphenicol-treated cells. The p21(waf1/cip1) was redistributed from the perinuclear region to the cytoplasm and co-localized with mitochondrial marker protein. Several morphological changes and activation of the senescence-associated biomarker, SA beta-galactosidase, were observed in these cells. Both p21(waf1/cip1) antisense and small interfering RNA could restore apoptotic-associated caspase 3 activity, PARP activation, and sensitivity to mitomycin-induced apoptosis. Similar effects were seen with other antibiotics that inhibit mitochondrial translation, including minocycline, doxycycline, and clindamycin. These findings suggested that mitochondrial stress causes resistance to apoptosis through a p21-dependent pathway.
Li
Ching-Hao
CH
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Tzeng
Su-Liang
SL
Cheng
Yu-Wen
YW
Kang
Jaw-Jou
JJ
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence; D002701:Chloramphenicol / Q000494:pharmacology*; D002981:Clindamycin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051545:Cyclooxygenase 1; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D004318:Doxycycline / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase; D017930:Genes, Reporter; D006801:Humans; D008564:Membrane Potentials; D008565:Membrane Proteins; D008856:Microscopy, Fluorescence; D008911:Minocycline / Q000494:pharmacology; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D016685:Mitomycin / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012270:Ribosomes / Q000737:chemistry; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D000900:Anti-Bacterial Agents; D015415:Biomarkers; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D002981:Clindamycin; D016685:Mitomycin; D012313:RNA; D002701:Chloramphenicol; D045304:Cytochromes c; D004247:DNA; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011065:Poly(ADP-ribose) Polymerases; D001616:beta-Galactosidase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D008911:Minocycline; D004318:Doxycycline