Abstract
β-Lapachone activates multiple cell death mechanisms including apoptosis, autophagy and necrotic cell death in cancer cells. In this study, we investigated β-lapachone-induced cell death and the underlying mechanisms in human hepatocellular carcinoma SK-Hep1 cells. β-Lapachone markedly induced cell death without caspase activation. β-Lapachone increased PI uptake and HMGB-1 release to extracellular space, which are markers of necrotic cell death. Necrostatin-1 (a RIP1 kinase inhibitor) markedly inhibited β-lapachone-induced cell death and HMGB-1 release. In addition, β-lapachone activated poly (ADP-ribosyl) polymerase-1(PARP-1) and promoted AIF release, and DPQ (a PARP-1 specific inhibitor) or AIF siRNA blocked β-lapachone-induced cell death. Furthermore, necrostatin-1 blocked PARP-1 activation and cytosolic AIF translocation. We also found that β-lapachone-induced reactive oxygen species (ROS) production has an important role in the activation of the RIP1-PARP1-AIF pathway. Finally, β-lapachone-induced cell death was inhibited by dicoumarol (a NQO-1 inhibitor), and NQO1 expression was correlated with sensitivity to β-lapachone. Taken together, our results demonstrate that β-lapachone induces programmed necrosis through the NQO1-dependent ROS-mediated RIP1-PARP1-AIF pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis Inducing Factor / genetics
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Apoptosis Inducing Factor / metabolism*
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Carcinoma, Hepatocellular / enzymology*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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HMGB1 Protein / metabolism
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Humans
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Liver Neoplasms / enzymology*
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Liver Neoplasms / genetics
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Liver Neoplasms / pathology
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NAD(P)H Dehydrogenase (Quinone) / genetics
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NAD(P)H Dehydrogenase (Quinone) / metabolism
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Naphthoquinones / pharmacology*
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Necrosis
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Nuclear Pore Complex Proteins / antagonists & inhibitors
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Nuclear Pore Complex Proteins / genetics
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Nuclear Pore Complex Proteins / metabolism*
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerase Inhibitors
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism*
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Protein Kinase Inhibitors / pharmacology
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Protein Transport
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RNA Interference
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RNA-Binding Proteins / antagonists & inhibitors
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Reactive Oxygen Species / metabolism
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Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
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Signal Transduction / drug effects
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Time Factors
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Transfection
Substances
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AGFG1 protein, human
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AIFM1 protein, human
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Antineoplastic Agents
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Apoptosis Inducing Factor
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HMGB1 Protein
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HMGB1 protein, human
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Naphthoquinones
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Nuclear Pore Complex Proteins
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Poly(ADP-ribose) Polymerase Inhibitors
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Protein Kinase Inhibitors
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RNA-Binding Proteins
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Reactive Oxygen Species
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beta-lapachone
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NAD(P)H Dehydrogenase (Quinone)
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NQO1 protein, human
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PARP1 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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RIPK1 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinases