β-Lapachone induces programmed necrosis through the RIP1-PARP-AIF-dependent pathway in human hepatocellular carcinoma SK-Hep1 cells
Open accessAbstract
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.
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Upon induction of necroptosis by TRAIL or β-lapachone, activated RIPK1 and RIPK3 appear to stimulate PARP1 enzymatic activity and promote ATP depletion and/or AIF release.
“upon induction of necroptosis by TRAIL or β lapachone (an ortho naphthoquinone with antineoplastic activity) [683], activated RIPK1 and RIPK3 appear to stimulate the enzymatic activity of PARP1 and hence promote ATP depletion and/or AIF release [684, 685].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [684]
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- Authors
- Park, E. J., Min, K.-J., Lee, T.-J., Yoo, Y. H., Kim, Y.-S., & Kwon, T. K.
- Affiliations
- Keimyung University (KR)
- Yeungnam University College (KR)
- Dong-A University (KR)
- Ajou University (KR)
- Corresponding author
- Kwon, T K
- Venue
- Cell Death & Disease
- Published
- 2014-05-15
- Volume
- 5
- Issue
- 5
- Pages
- e1230-e1230
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC4047891
- OpenAlex
- W2043947838
- Cited by
- 105
- References
- 39
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 9 · 2023: 9 · 2022: 8 · 2021: 9 · 2020: 7 · 2019: 6 · 2018: 9 · 2017: 11 · 2016: 14 · 2015: 14 · 2014: 3
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Death and Disease (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- AJOU Open Repository (Ajou University) (submittedVersion)
- KUMeL Repository (Keimyung University) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- β-lapachone, necroptosis, RIP1 kinase, PARP1, AIF translocation, hepatocellular carcinoma, SK-Hep-1 cells, reactive oxygen species, NQO1, necrostatin-1, caspase-independent cell death, dicumarol
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Poly (ADP-Ribose) Polymerase-1, Antineoplastic Agents, Dose-Response Relationship, Drug, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Naphthoquinones, Necrosis, Poly(ADP-ribose) Polymerases, Time Factors, Transfection, Signal Transduction, RNA-Binding Proteins, NAD(P)H Dehydrogenase (Quinone), Reactive Oxygen Species, Protein Transport, HMGB1 Protein, Nuclear Pore Complex Proteins, RNA Interference, Cell Line, Tumor, Protein Kinase Inhibitors, Apoptosis Inducing Factor, Receptor-Interacting Protein Serine-Threonine Kinases
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