?-Lapachone induces programmed necrosis through the RIP1-PARP-AIF-dependent
pathway in human hepatocellular carcinoma SK-Hep1 cells
#MMPMID24832602
Park EJ
; Min KJ
; Lee TJ
; Yoo YH
; Kim YS
; Kwon TK
Cell Death Dis
2014[May]; 5
(5
): e1230
PMID24832602
show ga
?-Lapachone activates multiple cell death mechanisms including apoptosis,
autophagy and necrotic cell death in cancer cells. In this study, we investigated
?-lapachone-induced cell death and the underlying mechanisms in human
hepatocellular carcinoma SK-Hep1 cells. ?-Lapachone markedly induced cell death
without caspase activation. ?-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 ?-lapachone-induced cell death and
HMGB-1 release. In addition, ?-lapachone activated poly (ADP-ribosyl)
polymerase-1(PARP-1) and promoted AIF release, and DPQ (a PARP-1 specific
inhibitor) or AIF siRNA blocked ?-lapachone-induced cell death. Furthermore,
necrostatin-1 blocked PARP-1 activation and cytosolic AIF translocation. We also
found that ?-lapachone-induced reactive oxygen species (ROS) production has an
important role in the activation of the RIP1-PARP1-AIF pathway. Finally,
?-lapachone-induced cell death was inhibited by dicoumarol (a NQO-1 inhibitor),
and NQO1 expression was correlated with sensitivity to ?-lapachone. Taken
together, our results demonstrate that ?-lapachone induces programmed necrosis
through the NQO1-dependent ROS-mediated RIP1-PARP1-AIF pathway.
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