Endoplasmic Reticulum Stress-Induced JNK Activation Is a Critical Event Leading to Mitochondria-Mediated Cell Death Caused by β-Lapachone Treatment

Abstract

Backgroundβ-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.Methodology/Principal Findingsβ-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/SignificanceOur 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.

Comparative assessment of the apoptotic potential of silver nanoparticles synthesized by Bacillus tequilensis and Calocybe indica in MDA-MB-231 human breast cancer cells: targeting p53 for anticancer therapy

“…75 The results from our experiments and the previous literature suggest that AgNPs can reduce the membrane potential of MDA-MB-231 cells. 73 …”

The Small GTPases Regulate HMC05-Induced NQO-1 Expression with an Antioxidant Effect in Smooth Muscle Cells

“…After serum starvation for 18 h, the cells were pretreated with HMC05 in the presence or absence of inhibitor for 1 h. The various concentrations of XO (10,20,30,40 and 50 munit/mL) with 0.5 mM xanthine were added to each well at 1 h after HMC05 treatment, after which the cells were incubated for an additional 18 h. Next, MTT (5 mg/mL) was incubated for an additional 2 h. The cell culture medium was then aspirated and the cells were solubilized in 200 µL dimethyl sulfoxide. Finally, an absorbance of 550 nm was measured using an ELISA reader (Bio-Tek Instruments, Winooski, VT, U.S.A.).…”

“…16,19,20) To identify the signaling pathway involved in HMC05-mediated NQO-1 induction, we assessed the effects of selective chemical inhibitors of signaling via MAPKs, PI3K, GGTase 1 and farnesyltransferase (FTase). Interestingly, the inhibitors of extracellular signal-regulated kinase (ERK) (PD98059), p38 MAPK (SB203580), JNK (JNK inhibitor II) and PI3K (LY294001 and wortmannin) had no effects on HMC05-mediated NQO-1 induction (Fig.…”

Nanoscale Metal Particles as Nanocarriers in Targeted Drug Delivery System

“…Interestingly, surface chemistry role during clearance or uptake in circulation accommodates the facilitation of nanotherapeutic carriers when an abundance of small nanoparticles exist within the malignancies [37]. Studies revealed that nanoscale Ag particles had shown a prolonged circulation type of the half-life nanoparticles which can escape from affected cell in the tissue effectively.…”