title: Peroxiredoxin 1 knockdown potentiates β-lapachone cytotoxicity through modulation of reactive oxygen species and mitogen-activated protein kinase signals.
abstract: Peroxiredoxin (Prx) 1 is a member of the thiol-specific peroxidases family and plays diverse roles such as H2O2 scavenger, redox signal transducer and molecular chaperone. Prx1 has been reported to be involved in protecting cancer cells against various therapeutic challenges. We investigated how modulations of intracellular redox system affect cancer cell sensitivity to reactive oxygen species (ROS)-generating drugs. We observed that stable and transient Prx1 knockdown significantly enhanced HeLa cell sensitivity to β-lapachone (β-lap), a potential anticancer agent. Prx1 knockdown markedly potentiated 2 µM β-lap-induced cytotoxicity through ROS accumulation. This effect was largely NAD(P)H:quinone oxidoreductase 1 dependent and associated with a decrease in poly(ADP-ribose) polymerase 1 protein levels, phosphorylation of JNK, p38 and Erk proteins in mitogen-activated protein kinase (MAPK) pathways and a decrease in thioredoxin 1 (Trx1) protein levels. Trx1 serves as an electron donor for Prx1 and is overexpressed in Prx1 knockdown cells. Based on the fact that Prx1 is a major ROS scavenger and a partner of at least ASK1 and JNK, two key components of MAPK pathways, we propose that Prx1 knockdown-induced sensitization to β-lap is achieved through combined action of accumulation of ROS and enhancement of MAPK pathway activation, leading to cell apoptosis. These data support the view that modulation of intracellular redox state could be an alternative approach to enhance cancer cell sensitivity to ROS-generating drugs or to overcome some types of drug resistance.
authors.affiliation: Centre National de la Recherche Scientifique, UMR 3348 Genotoxic Stress and Cancer, Orsay, France.
authors.forename: Tiantian
authors.initials: T
authors.lastname: He
authors.forename: Agata
authors.initials: A
authors.lastname: Banach-Latapy
authors.forename: Laurence
authors.initials: L
authors.lastname: Vernis
authors.forename: Michèle
authors.initials: M
authors.lastname: Dardalhon
authors.forename: Roland
authors.initials: R
authors.lastname: Chanet
authors.forename: Meng-Er
authors.initials: ME
authors.lastname: Huang
mesh_terms: D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D054464:Peroxiredoxins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013879:Thioredoxins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D009285:Naphthoquinones; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018894:Reverse Transcriptase Inhibitors; D013879:Thioredoxins; C014638:beta-lapachone; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases