title: Endoplasmic reticulum stress-induced JNK activation is a critical event leading to mitochondria-mediated cell death caused by β-lapachone treatment.
abstract: BACKGROUND
  β-Lapachone (β-lap) is a bioreductive agent that is activated by the two-electron reductase NAD(P)H quinone oxidoreductase 1 (NQO1). Although β-lap has been reported to induce apoptosis in various cancer types in an NQO1-dependent manner, the signaling pathways by which β-lap causes apoptosis are poorly understood.
  
  
  RESULTS
  β-Lap-induced apoptosis and related molecular signaling pathways in NQO1-negative and NQO1-overexpressing MDA-MB-231 cells were investigated. Pharmacological inhibitors or siRNAs against factors involved in β-lap-induced apoptosis were used to clarify the roles played by such factors in β-lap-activated apoptotic signaling pathways. β-Lap leads to clonogenic cell death and apoptosis in an NQO1-dependent manner. Treatment of NQO1-overexpressing MDA-MB-231 cells with β-lap causes rapid disruption of mitochondrial membrane potential, nuclear translocation of AIF and Endo G from mitochondria, and subsequent caspase-independent apoptotic cell death. siRNAs targeting AIF and Endo G effectively attenuate β-lap-induced clonogenic and apoptotic cell death. Moreover, β-lap induces cleavage of Bax, which accumulates in mitochondria, coinciding with the observed changes in mitochondria membrane potential. Pretreatment with Salubrinal (Sal), an endoplasmic reticulum (ER) stress inhibitor, efficiently attenuates JNK activation caused by β-lap, and subsequent mitochondria-mediated cell death. In addition, β-lap-induced generation and mitochondrial translocation of cleaved Bax are efficiently blocked by JNK inhibition.
  
  
  CONCLUSIONS
  Our results indicate that β-lap triggers induction of endoplasmic reticulum (ER) stress, thereby leading to JNK activation and mitochondria-mediated apoptosis. The signaling pathways that we revealed in this study may significantly contribute to an improvement of NQO1-directed tumor therapies.
authors: Department of Microbiology, College of Medicine, Center for Advanced Medical Education by BK21 Project, Inha University, Incheon, Republic of Korea.
authors: Hyemi
authors: H
authors: Lee
authors: Moon-Taek
authors: MT
authors: Park
authors: Bo-Hwa
authors: BH
authors: Choi
authors: Eun-Taex
authors: ET
authors: Oh
authors: Min-Jeong
authors: MJ
authors: Song
authors: Jeonghun
authors: J
authors: Lee
authors: Chulhee
authors: C
authors: Kim
authors: Byung Uk
authors: BU
authors: Lim
authors: Heon Joo
authors: HJ
authors: Park
mesh_terms: D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D034741:RNA, Small Interfering
chemical_list: D009285:Naphthoquinones; D034741:RNA, Small Interfering; C014638:beta-lapachone; D048031:JNK Mitogen-Activated Protein Kinases