Caffeine sensitizes human H358 cell line to p53-mediated apoptosis by inducing mitochondrial translocation and conformational change of BAX protein.
The mechanisms involved in p53-mediated cell death remain controversial. In the present study, we investigated this cell death pathway by stably transfecting the p53-null H358 cell line with a tetracycline-dependent wild type p53-expressing vector. Restoration of p53 triggered a G(2)/M cell cycle arrest and enhanced BAX protein expression, without inducing apoptosis or potentiating the cytotoxic effect of etoposide, vincristine, and cis-platinum. Accordingly, overexpression of BAX in H358 cells, through stable transfection of a tetracycline-regulated expression vector, did not induce cell death. Interestingly, the methylxanthine caffeine (4 mm) promoted the translocation of BAX from the cytosol to the mitochondria. In the setting of an overexpression of BAX, caffeine induced a conformational change of the protein and apoptosis. The consequences of caffeine were independent of its cell cycle-related activities. All together, caffeine synergizes with p53 for inducing cell death through a cell cycle-independent mechanism, involving mitochondrial translocation and conformational change of BAX protein.
Dubrez
L
L
Groupe de Recherche sur le Cancer du Poumon, INSERM E9924, Institut Albert Bonniot, 38706 La Tronche Cedex, France.
Coll
J L
JL
Hurbin
A
A
Solary
E
E
Favrot
M C
MC
D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002110:Caffeine / Q000494:pharmacology*; D016923:Cell Death; D002460:Cell Line; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011487:Protein Conformation; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000737:chemistry*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014750:Vincristine / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; D000697:Central Nervous System Stimulants; D019384:Nucleic Acid Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D014970:Xanthines; D051028:bcl-2-Associated X Protein; C008514:methylxanthine; D002110:Caffeine; D014750:Vincristine; D005047:Etoposide; D002945:Cisplatin