A new lactoferrin- and iron-dependent lysosomal death pathway is induced by benzo[a]pyrene in hepatic epithelial cells.
While lysosomal disruption seems to be a late step of necrosis, a moderate lysosomal destabilization has been suggested to participate early in the apoptotic cascade. The origin of lysosomal dysfunction and its precise role in apoptosis or apoptosis-like process still needs to be clarified, especially upon carcinogen exposure. In this study, we focused on the implication of lysosomes in cell death induced by the prototype carcinogen benzo[a]pyrene (B[a]P; 50 nM) in rat hepatic epithelial F258 cells. We first demonstrated that B[a]P affected lysosomal morphology (increase in size) and pH (alkalinization), and that these changes were involved in caspase-3 activation and cell death. Subsequently, we showed that lysosomal modifications were partly dependent on mitochondrial dysfunction, and that lysosomes together with mitochondria participate in B[a]P-induced oxidative stress. Using two iron chelators (desferrioxamine and deferiprone) and siRNA targeting the lysosomal iron-binding protease lactoferrin, we further demonstrated that both lysosomal iron content and lactoferrin were required for caspase-3 activation and apoptosis-like cell death.
Gorria
Morgane
M
INSERM U620, Toxicity of polycyclic aromatic hydrocarbons group (Equipe Labellisée Ligue contre le Cancer), Faculté de Pharmacie, Université Rennes I, 2 avenue Pr. Léon Bernard, Rennes cedex, France.
Tekpli
Xavier
X
Rissel
Mary
M
Sergent
Odile
O
Huc
Laurence
L
Landvik
Nina
N
Fardel
Olivier
O
Dimanche-Boitrel
Marie-Thérèse
MT
Holme
Jørn A
JA
Lagadic-Gossmann
Dominique
D
D000165:Acridine Orange / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001564:Benzo(a)pyrene / Q000737:chemistry / Q000633:toxicity*; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D000077543:Deferiprone; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D007501:Iron / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D007781:Lactoferrin / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008854:Microscopy, Electron; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014162:Transfection
D002273:Carcinogens; D007502:Iron Chelating Agents; D011728:Pyridones; D034741:RNA, Small Interfering; D000077543:Deferiprone; D001564:Benzo(a)pyrene; D007501:Iron; D007781:Lactoferrin; D053148:Caspase 3; D000165:Acridine Orange; D003676:Deferoxamine