AKT/mTOR and c-Jun N-terminal kinase signaling pathways are required for chrysotile asbestos-induced autophagy

Lin, Ziying; Li, Shipeng; Kamp, David W.; Wang, Yahong; Huang, He; Zhou, Xu; Li, Donghong; Yang, Liting; Zhao, Bin; Liu, Gang

doi:10.1016/j.freeradbiomed.2014.04.004

Cited by 26 publications

(24 citation statements)

References 57 publications

(80 reference statements)

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“…A previous study by our group revealed that p53 mediated PM-induced alveolar epithelial cell mitochondria-regulated apoptosis (13). It was also confirmed that the Akt/mTOR and c-Jun N-terminal kinase (JNK) signaling pathways were involved in chrysotile asbestos-induced autophagy in human lung epithelial cells (A549) (14). In the present study, the effect of PM 2.5 on the induction of autophagy in vitro and the potential underlying mechanisms were evaluated.…”

Section: Introductionsupporting

confidence: 64%

Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells

Wang

et al. 2015

Molecular Medicine Reports

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Abstract. Particulate matter 2.5 (PM 2.5 ) is a significant risk factor for asthma. A recent study revealed that autophagy was associated with asthma pathogenesis. However, the specific mechanisms underlying PM 2.5 -induced autophagy in asthma have remained elusive. In the present study, PM 2.5 -induced autophagy was evaluated in Beas-2B human bronchial epithelial cells and the potential molecular mechanisms were investigated. Using electron microscopy, immunofluorescence staining and immunoblot studies, it was confirmed that PM 2.5 induced autophagy in Beas-2B cells as a result of PM 2.5 -mediated inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in Beas-2B cells. LY294002, a PI3K inhibitor, reduced the accumulation of microtubule-associated protein 1 light chain 3 II and attenuated the effect of PM 2.5 . Phosphorylated (p-)p38, p-extracellular signal-regulated kinase and p-c-Jun N-terminal kinase were dephosphorylated following exposure to PM 2.5 . The roles of p53, reactive oxygen species scavenger tetramethylthiourea and autophagy inhibitor 3-methyladenine in PM 2.5 -induced autophagy in Beas-2B cells were also investigated. The results suggested that the PI3K/Akt/mTOR signaling pathway may be a key contributor to PM 2.5 -induced autophagy in Beas-2B cells. The results of the present study therefore provided an a insight into potential future clinical applications targeting these signaling pathways, for the prevention and/or treatment of PM 2.5 -induced lung diseases. IntroductionAcute and chronic exposure to particulate matter (PM), particularly fine particles with aerodynamic diameters of ≤2.5 µm PM 2.5 , has been shown to increase the number of hospital admissions for respiratory causes amongst the general population (1). Evidence obtained from environmental and epidemiological studies has revealed a marked association between fine particulate air pollution and multiple health issues, including respiratory illnesses (for example, respiratory track inflammation, asthma, acute bronchitis and lung cancer) as well as cardiovascular disease mortality (2-4).Increasing evidence supporting a link between traffic-associated air pollution and the incidence of childhood asthma has emerged; however, published estimates highlight the variability observed between populations (5,6). Asthma is a common worldwide respiratory symptom complex, frequently involving airway inflammation, which results in clinically significant physiological airway dysfunction. Asthma pathogenesis is complex, and multiple factors have roles in the development of the disease (7).Autophagy describes an evolutionarily conserved and tightly regulated lysosomal pathway, responsible for the degradation of macromolecules, including proteins, glycogen, lipids, nucleotides and organelles, via several complex pathways (8).Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial ...

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Section: Introductionsupporting

confidence: 64%

Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells

Wang

et al. 2015

Molecular Medicine Reports

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“…Many reported studies support the conclusion that MAPK8/9 plays an essential role in the promotion of autophagy [5–23]. In contrast, our analysis does not indicate a major role for MAPK8/9 in starvation-induced autophagy.…”

Section: Discussionsupporting

confidence: 64%

“…This mechanism of MAPK8 signaling is mediated by BCL2 (B cell leukemia/lymphoma 2) phosphorylation (on Thr69, Ser70, and Ser87) that disrupts the interaction of BCL2 with BECN1 (beclin 1, autophagy related) and initiates BECN1-dependent autophagy [5]. Subsequent studies have provided strong support for this role of MAPK8 in autophagy [6–19], although contributing roles for MAPK9 [20–23] and alternative potential functions of MAPK8 related to autophagy have also been reported [24–29]. …”

Section: Introductionmentioning

confidence: 99%

Role of the MAPK/cJun NH ₂ -terminal kinase signaling pathway in starvation-induced autophagy

et al. 2018

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Autophagy is required for cellular homeostasis and can determine cell viability in response to stress. It is established that MTOR is a master regulator of starvation-induced macroautophagy/autophagy, but recent studies have also implicated an essential role for the MAPK8/cJun NH2-terminal kinase 1 signal transduction pathway. We found that MAPK8/JNK1 and MAPK9/JNK2 were not required for autophagy caused by starvation or MTOR inhibition in murine fibroblasts and epithelial cells. These data demonstrate that MAPK8/9 has no required role in starvation-induced autophagy. We conclude that the role of MAPK8/9 in autophagy may be context-dependent and more complex than previously considered.Abbreviations: AKT: thymoma viral proto-oncogene;ALB: albumin; ATG4: autophagy related 4; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1, autophagy related; BNIP3: BCL2/adenovirus E1B interacting protein 3; CQ: chloroquine diphosphate; DMEM: Dulbecco’s modified Eagle’s medium; EDTA: ethylenediaminetetraacetic acid; EBSS: Earle’s balanced salt solution; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HRAS: Harvey rat sarcoma virus oncogene; IgG: Immunoglobulin G; MAPK3/ERK1: mitogen-activated protein kinase 3; MAPK8/JNK1: mitogen-activated protein kinase 8; MAPK9/JNK2: mitogen-activated protein kinase 9; MAPK10/JNK3: mitogen-activated protein kinase 10; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; RPS6KB1/p70: ribosomal protein S6 kinase, polypeptide 1; PPARA: peroxisome proliferator activated receptor alpha; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TORC1: target of rapamycin complex 1; TORC2: target of rapamycin complex 2; TRP53: transforming related protein 53; TUBA: tubulin alpha; UV: ultraviolet; WT: wild-type

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“…We speculate that NF-κB p65 regulated the expression of the autophagyassociated protein LC3B and controlled the expression of p53 to control the expression of Bcl-2 family proteins in BMA155Cl-induced HepG-2 cells. Considering the complexity of intracellular signal transduction, other signaling proteins, such as p38 and AKT, may also play important roles in BMA155Cl-induced autophagy and apoptosis in HepG-2 cells [42] . Our results suggest that the BMA-155Cl-induced inhibition of HepG-2 cell growth via autophagy and apoptosis might be a promising anti-tumor candidate.…”

Section: Discussionmentioning

confidence: 99%

Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway

Sun

et al. 2017

Acta Pharmacol Sin

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Bisindolylmaleimides, a series of derivatives of a PKC inhibitor staurosporine, exhibit potential as anti-cancer drugs and have received considerable attention in clinical trials. This study aims to investigate the effects of a bisindolylmaleimide alkaloid 155Cl (BMA-155Cl) with a novel structure on autophagy and apoptosis in human hepatocarcinoma HepG-2 cells in vitro and in vivo. The cell poliferation was assessed with a MTT assay. Autophagy was evaluated by MDC staining and TEM analysis. Apoptosis was investigated using Annexin V-FITC/PI and DAPI staining. The antitumor effects were further evaluated in nude mice bearing HepG-2 xenografts, which received BMA-155Cl (10, 20 mg/kg, ip) for 18 days. Autophagy-and apoptosis-associated proteins and their mRNA levels were examined with Western blotting, immunohistochemistry, and RT-PCR. BMA-155Cl (2.5-20 μmol/L) inhibited the growth of HepG-2 cells with IC 50 values of 16.62±1.34, 12.21±0.83, and 8.44±1.82 μmol/L at 24, 48, and 72 h, respectively. Furthermore, BMA155Cl (5-20 μmol/L) dose-dependently induced autophagy and apoptosis in HepG-2 cells. The formation of autophagic vacuoles was induced by BMA-155Cl (10 μmol/L) at approximately 6 h and peaked at approximately 15 h. Pretreatment with 3-MA potentiated BMA-155Cl-mediated apoptotic cell death. This compound dose-dependently increased the mRNA and protein levels of Beclin-1, NF-κB p65, p53, and Bax, but decreased the expression of IκB and Bcl-2. Pretreatment with BAY 11-7082, a specific inhibitor of NF-κB p65, blocked BMA-155Cl-induced expression of autophagy-and apoptosis-associated proteins. BMA-155Cl administration effectively suppressed the growth of HepG-2 xenografts in vivo, and increased the protein expression levels of LC3B, Beclin-1, NF-κB p65, and Bax in vivo. We conclude that the NF-κB p65 pathway is involved in BMA-155Cl-triggered autophagy, followed by apoptosis in HepG-2 cells in vitro and in vivo. Hence, BMA-155Cl could be a promising pro-apoptotic candidate for developing as a novel anti-cancer drug.

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AKT/mTOR and c-Jun N-terminal kinase signaling pathways are required for chrysotile asbestos-induced autophagy

Cited by 26 publications

References 57 publications

Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells

Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells

Role of the MAPK/cJun NH ₂ -terminal kinase signaling pathway in starvation-induced autophagy

Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway

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AKT/mTOR and c-Jun N-terminal kinase signaling pathways are required for chrysotile asbestos-induced autophagy

Cited by 26 publications

References 57 publications

Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells

Particulate matter 2.5 induces autophagy via inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin kinase signaling pathway in human bronchial epithelial cells

Role of the MAPK/cJun NH 2 -terminal kinase signaling pathway in starvation-induced autophagy

Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway

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Role of the MAPK/cJun NH ₂ -terminal kinase signaling pathway in starvation-induced autophagy