beta-Lapachone induces programmed necrosis through the RIP1-PARP-AIF-dependent pathway in human hepatocellular carcinoma SK-Hep1 cells

Title
beta-Lapachone induces programmed necrosis through the RIP1-PARP-AIF-dependent pathway in human hepatocellular carcinoma SK-Hep1 cells
Author(s)
권택규[권택규]박은정[박은정]민경진[민경진]이태진유영현[유영현]김유선[김유선]
Keywords
PROSTATE-CANCER CELLS; CASPASE-INDEPENDENT NECROPTOSIS; RECEPTOR-INTERACTING PROTEIN; OXIDOREDUCTASE 1 NQO1; INDUCED APOPTOSIS; HYDROGEN-PEROXIDE; TUMOR-CELLS; DEATH; ACTIVATION; GENE
Issue Date
201405
Publisher
NATURE PUBLISHING GROUP
Citation
CELL DEATH & DISEASE, v.5
Abstract
beta-Lapachone activates multiple cell death mechanisms including apoptosis, autophagy and necrotic cell death in cancer cells. In this study, we investigated beta-lapachone-induced cell death and the underlying mechanisms in human hepatocellular carcinoma SK-Hep1 cells. beta-Lapachone markedly induced cell death without caspase activation. beta-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 beta-lapachone-induced cell death and HMGB-1 release. In addition, beta-lapachone activated poly (ADP-ribosyl) polymerase-1(PARP-1) and promoted AIF release, and DPQ (a PARP-1 specific inhibitor) or AIF siRNA blocked beta-lapachone-induced cell death. Furthermore, necrostatin-1 blocked PARP-1 activation and cytosolic AIF translocation. We also found that beta-lapachone-induced reactive oxygen species (ROS) production has an important role in the activation of the RIP1-PARP1-AIF pathway. Finally, beta-lapachone-induced cell death was inhibited by dicoumarol (a NQO-1 inhibitor), and NQO1 expression was correlated with sensitivity to beta-lapachone. Taken together, our results demonstrate that beta-lapachone induces programmed necrosis through the NQO1-dependent ROS-mediated RIP1-PARP1-AIF pathway.
URI
http://hdl.handle.net/YU.REPOSITORY/32160http://dx.doi.org/10.1038/cddis.2014.202
ISSN
2041-4889
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의과대학 > 해부학교실 > Articles
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