Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways

Zhang, Li; Wang, Handong; Xu, Jianguo; Zhu, Jiaan; Ding, Ke

doi:10.1016/j.toxlet.2014.05.015

Cited by 130 publications

(112 citation statements)

References 38 publications

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“…It was found that inhibition of ROS activity indeed decreased HBx-triggered JNK activation and autophagosome formation. A variety of reports have indicated that ROS activation often leads to inhibition of the AKT/mTOR axis (62,63); however, our data show that HBx overexpression in HepG2 cells not only leads to the generation of ROS but also activates class I PI3K/AKT/mTOR signaling. This scenario might be due to the inhibitory effect of HBx on PTEN, a negative regulator of AKT activation, as reported by Ha and Yu (50).…”

Section: Discussioncontrasting

confidence: 68%

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Zhong

Shu

Dai

et al. 2017

J Virol

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Autophagy is closely associated with the regulation of hepatitis B virus (HBV) replication. HBV X protein (HBx), a multifunctional regulator in HBV-associated biological processes, has been demonstrated to be crucial for autophagy induction by HBV. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we demonstrated that HBx induced autophagosome formation independently of the class I phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway. In contrast, the class III PI3K(VPS34)/beclin-1 pathway was revealed to be critical for HBx-induced autophagosome formation. Further study showed that HBx did not affect the level of VPS34 and beclin-1 expression but inhibited beclin-1/Bcl-2 association, and c-Jun NH2-terminal kinase (JNK) signaling was found to be important for this process. Moreover, it was found that HBx treatment led to the generation of reactive oxygen species (ROS), and inhibition of ROS activity abrogated both JNK activation and autophagosome formation. Of importance, ROS-JNK signaling was also revealed to play an important role in HBV-induced autophagosome formation and subsequent HBV replication. These data may provide deeper insight into the mechanisms of autophagy induction by HBx and help in the design of new therapeutic strategies against HBV infection.IMPORTANCE HBx plays a key role in diverse HBV-associated biological processes, including autophagy induction. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we found that HBx induced autophagy independently of the class I PI3K/AKT/mTOR signaling pathway, while the class III PI3K(VPS34)/beclin-1 pathway was revealed to be crucial for this process. Further data showed that ROS-JNK activation by HBx resulted in the release of beclin-1 from its association with Bcl-2 to form a complex with VPS34, thus enhancing autophagosome formation. Of importance, ROS-JNK signaling was also demonstrated to be critical for HBV replication via regulation of autophagy induction. These data help to elucidate the molecular mechanisms of autophagy induction by HBx/HBV and might be useful for designing novel therapeutic approaches to HBV infection.KEYWORDS HBV X protein, autophagy, signaling pathway, viral replication H epatitis B virus (HBV) is an important human pathogen that can cause a wide spectrum of liver diseases, including hepatitis, liver cirrhosis, and hepatocellular carcinoma (1, 2). The HBV genome is about 3.2 kb in length, carrying four genes named

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Section: Discussioncontrasting

confidence: 68%

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Zhong

Shu

Dai

et al. 2017

J Virol

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“…Phosphorylation of p70S6K can promote mRNA translation and the cell cycle (26). Restraining mTOR can lead to blocked p70S6K phosphorylation and translation, thereby causing cell cycle arrest and induction of apoptosis (27,28). Chang et al (7) reported that treatment with propofol induced autophagy and increased angiogenic capacity of human umbilical vascular endothelial cells through PI3K/Akt and mTOR.…”

Section: Discussionmentioning

confidence: 99%

Propofol promotes apoptosis and suppresses the HOTAIR-mediated mTOR/p70S6K signaling pathway in melanoma cells

et al. 2017

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Abstract.Propofol is an intravenous anesthetic, which is widely used in clinical anesthesia induction and maintenance and is critical in the sedation of patients. However, the functions and mechanisms of propofol on apoptosis of melanoma cells remain unclear. The present study investigated whether propofol promotes cell apoptosis and suppresses the HOX transcript antisense RNA (HOTAIR)-mediated mechanistic target of rapamycin (mTOR) pathway in melanoma cells. B16F10 cells were cultured with different concentrations (0-10 µM) of propofol for 24 or 48 h. Proliferation and apoptosis of B16F10 cells were detected using MTT assay and flow cytometry. The pcDNA 3

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“…A mutual relationship exists between redox homeostasis of the cell and the activity of the mTOR/autophagy axis. In vitro studies showed that increased levels of OS cause a reduction of mTOR activity, thus inducing the formation of autophagosomes in order to remove potential ROS-induced damage, defective mitochondria or harmed cellular components [14,15,29]. …”

Section: Discussionmentioning

confidence: 99%

“…Indeed, free radicals are both upstream and downstream signals of mTOR and numerous feedback and feedforward loops exist. On one hand, increased levels of reactive oxygen species (ROS) are involved in the regulation of autophagic survival signals and death processes [14], and these effects can be reverted by antioxidant treatment [15]. On the other hand, it is conceivable that autophagy provides protection against oxidative damage.…”

Section: Introductionmentioning

confidence: 99%

Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down's Syndrome

et al. 2015

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Background: Neurodegenerative diseases are characterized by increased levels of oxidative stress and an altered mammalian target of rapamycin (mTOR)/autophagy axis; however, the mutual relationship between these two events is controversial. Previous studies in Down's syndrome (DS) and Alzheimer's disease (AD) suggested that the accumulation of protein oxidative damage results from the increased free radical production, mainly related to metabolic alterations, mitochondrial degeneration and amyloid-β deposition, and aberrant activity of protein degradative systems. Summary: This study analyzed mTOR signaling in Ts65Dn mice, a model of DS, at 6 and 12 months of age compared with euploid mice showing the early aberrant hyperphosphorylation of mTOR coupled with the reduction of autophagosome formation. Moreover, the evaluation of protein oxidation shows an increase in protein nitration and protein-bound 4-hydroxynonenal in 12-month-old Ts65Dn mice suggesting the potential involvement of altered autophagy in the buildup of protein oxidative damage. In addition, data obtained on cell culture support the protective role of autophagy in reducing protein oxidation. Key Messages: Overall, this study provides further evidence for the role of mTOR hyperactivation and reduced autophagy in the accumulation of protein oxidative damage during DS and AD pathologies.

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Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways

Cited by 130 publications

References 38 publications

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Propofol promotes apoptosis and suppresses the HOTAIR-mediated mTOR/p70S6K signaling pathway in melanoma cells

Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down's Syndrome

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Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways

Cited by 130 publications

References 38 publications

Reactive Oxygen Species-Mediated c-Jun NH 2 -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Reactive Oxygen Species-Mediated c-Jun NH 2 -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Propofol promotes apoptosis and suppresses the HOTAIR-mediated mTOR/p70S6K signaling pathway in melanoma cells

Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down's Syndrome

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Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction

Reactive Oxygen Species-Mediated c-Jun NH ₂ -Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction