Cadmium (Cd) toxicity is associated with endoplasmic reticulum (ER) stress-mediated apoptosis and autophagy. However, the regulatory mechanisms responsible for the signaling pathways initiated by Cd are incompletely understood. Here, we investigated the involvement of glycogen synthase kinase (GSK) 3αβ and mitogen-activated protein kinases (MAPKs) in Cd toxicity. Cd-exposed H460 cells exhibited activation of JNK, p38, PERK, and CHOP and induction of autophagy and apoptosis; in contrast, levels of these proteins were minimal in Cd-resistant H1299 cells. In H460 cells, genetic or pharmacological inhibition of JNK markedly enhanced CHOP, autophagy and apoptosis induced by Cd, which were reversed by overexpression of JNK1. Inhibition of p38 suppressed Cd-induced CHOP, and markedly inhibited autophagy via Atg5 downregulation. Cd-exposed H460 cells showed GSK3αβ phosphorylation at serine (Ser) and tyrosine (Tyr) residues, which was downregulated by a GSK3 inhibitor (SB216763) and by genetic silencing of GSK3β, subsequently suppressing JNK and p38 activation. However, H460 cells pretreated with lithium or overexpressing GSK3β exhibited enhanced JNK and p38 activation. Pretreatment of H460 cells with okadaic acid (a Ser/Thr phosphatase inhibitor) upregulated Cd-induced p-Ser GSK3αβ and enhanced CHOP, p-p38 and autophagy, whereas treatment with vanadate (a tyrosine phosphatase inhibitor) downregulated Cd-induced p-Ser GSK3αβ, enhanced p-JNK and downregulated CHOP and autophagy. Furthermore, H460 cells overexpressing a constitutively active GSK3β mutant (S9A) exhibited enhanced p-JNK and inhibited CHOP, whereas overexpression of constitutively inactive GSK3β (K85A) enhanced p-p38 and autophagy in response to Cd. Pretreatment with N-acetyl cysteine suppressed Cd-induced p-Ser/p-Tyr GSK3αβ and downstream pathways. These findings show that Cd toxicity is regulated by autophagy, which can be countered by prosurvival JNK and prodeath p38 MAPK activation through site-specific phosphorylation of GSK3αβ.
#1Wafa B'chir(INRA: Institut national de la recherche agronomique)H-Index: 8
#2Cédric Chaveroux(INRA: Institut national de la recherche agronomique)H-Index: 16
Last. Alain Bruhat(INRA: Institut national de la recherche agronomique)H-Index: 33
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Abstract CHOP encodes a ubiquitous transcription factor that is one of the most important components in the network of stress-inducible transcription. In particular, this factor is known to mediate cell death in response to stress. The focus of this work is to study its pivotal role in the control of cell viability according to the duration of a stress like amino acid starvation. We show that during the first 6 h of starvation, CHOP upregulates a number of autophagy genes but is not involved in ...
Cadmium is a widespread toxic pollutant of occupational and environmental concern because of its diverse toxic effects: extremely protracted biological half-life (approximately 20–30 years in humans), low rate of excretion from the body and storage predominantly in soft tissues (primarily, liver and kidneys). It is an extremely toxic element of continuing concern because environmental levels have risen steadily due to continued worldwide anthropogenic mobilization. Cadmium is absorbed in signifi...
#1Guang Jia(HMU: Harbin Medical University)H-Index: 7
#2Rui Kong(HMU: Harbin Medical University)H-Index: 13
Last. Bei Sun(HMU: Harbin Medical University)H-Index: 27
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Background c-Jun NH2-terminal kinases (JNKs) are strongly activated by a stressful cellular environment, such as chemotherapy and oxidative stress. Autophagy is a protein-degradation system in which double-membrane vacuoles called autophagosomes are formed. The autophagy-related gene Beclin 1 plays a key role in this process. We previously found that autophagy was induced by dihydroartemisinin (DHA) in pancreatic cancer cells. However, little is known about the complex relationship between ROS, ...
The spatial organisation of mitogen-activated protein kinase (MAPK) signalling by scaffold proteins is an important determinant of signalling specificity. Martinez-Lopez et al. show that pre-autophagosomal structures can also act as scaffolds, recruiting the MAPK ERK1/2 and regulating its phosphorylation.
and decreased LC3-II, suggesting that p-Tyr inhibits autophagy. PI3K inhibitors decreased Cd-induced p-Ser GSK-3αβ and LC3-II, whereas a Ser/Thr phosphatase inhibitor, okadaic acid, hyperphosphoryl- ated Ser residues, which accumulated in the nucleus and cytosol, and enhanced LC3-II. The general tyrosine kinase inhibitor gen- istein suppressed Cd-induced p-Tyr/p-Ser GSK-3α/β and LC3-II. Mouse lung tissues respond to long-term Cd exposure increased p-Tyr, downregulated LC3-II, and accumulated ful...
#1Wafa B'chir(INRA: Institut national de la recherche agronomique)H-Index: 8
#2Anne-Catherine Maurin(INRA: Institut national de la recherche agronomique)H-Index: 21
Last. Alain Bruhat(INRA: Institut national de la recherche agronomique)H-Index: 33
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In response to different environmental stresses, eIF2α phosphorylation represses global translation coincident with preferential translation of ATF4, a master regulator controlling the transcription of key genes essential for adaptative functions. Here, we establish that the eIF2α/ATF4 pathway directs an autophagy gene transcriptional program in response to amino acid starvation or endoplasmic reticulum stress. The eIF2α-kinases GCN2 and PERK and the transcription factors ATF4 and CHOP are also ...
Cellular stress elicited by the toxic metal Cd2+ does not coerce the cell into committing to die from the onset. Rather, detoxification and adaptive processes are triggered concurrently, allowing survival until normal function is restored. With high Cd2+, death pathways predominate. However, if sublethal stress levels affect cells for prolonged periods, as in chronic low Cd2+ exposure, adaptive and survival mechanisms may deregulate, such that tumorigenesis ensues. Hence, death and malignancy ar...
Quercetin, a ubiquitous bioactive plant flavonoid, has shown to exert a broad range of activities, such as apoptotic, antioxidant, and anti-inflammatory effects. Thus, flavonoids can mediate both cell protection and cell injury. Recently, quercetin has been reported to prevent the progression of emphysema in animal models through antioxidant and anti-inflammatory actions. These findings suggest that quercetin could be a potential treatment option for chronic obstructive pulmonary disease. Its cl...
In this study, BRL 3A cells were treated with different Cd concentrations (0, 10, 20, and 40 μmol/L) for 12 h and preincubated with or without N-acetyl-L-cysteine (NAC) (2 mmol/L) for 30 min, and cells were treated with Cd (0 and 20 μmol/L), pretreated with p38 inhibitor (SB203580), JNK (c-Jun NH2-terminal kinases) inhibitor (SP600125), and extracellular signal-regulated kinase (ERK) inhibitor (U0126) for 30 min, and then treated with 20 μmol/L Cd for 12 h. Cd decreased cell viability, SOD, and ...
#1Eric Keil(HHU: University of Düsseldorf)H-Index: 7
#2R Höcker(Otto-von-Guericke University Magdeburg)H-Index: 1
Last. Ingo Schmitz(Otto-von-Guericke University Magdeburg)H-Index: 40
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Autophagy is a lysosomal degradation pathway important for cellular homeostasis, mammalian development, cancer and immunity. Many molecular components of autophagy have been identified, but little is known about regulatory mechanisms controlling their effector functions. Here, we show that, in contrast to other p38 MAP kinase activators, the growth arrest and DNA damage 45 beta (Gadd45β)–MAPK/ERK kinase kinase 4 (MEKK4) pathway specifically directs p38 to autophagosomes. This process results in ...
Abstract Antioxidant enzymes are related to oral diseases. We investigated the roles of heme oxygenase-1 (HO-1) and catalase in cadmium (Cd)-induced oxidative stress and the underlying molecular mechanism in oral cancer cells. Exposing YD8 cells to Cd reduced the expression levels of catalase and superoxide dismutase 1/2 and induced the expression of HO-1 as well as autophagy and apoptosis, which were reversed by N -acetyl- l -cysteine (NAC). Cd-exposed YD10B cells exhibited milder effects than ...
This study examined the role of alpha-synuclein in regulating cadmium (Cd)-induced neurotoxicity using the N27 dopaminergic neuronal model of Parkinson’s disease (PD) that stably expresses wild-type human α-synuclein (α-Syn) or empty vector (Vec) control. We report that α-Syn significantly increased Cd-induced cytotoxicity as compared to Vec control cells upon 24 h exposure. To explore the cellular mechanisms, we examined oxidative stress, caspase activation, and Cd uptake and intracellular accu...
#1Qiuling Li(Capital Medical University)H-Index: 9
#2Hejing Hu(Capital Medical University)H-Index: 15
Last. Zhiwei Sun(Capital Medical University)H-Index: 28
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The adverse effects of silica nanoparticles are gaining attention due to their wide application in biomedicine. However, information about size-dependent toxicity induced by silica nanoparticles is insufficient. In this study, two size of nano-scale (40 nm, 60 nm) and one size of micro-scale (200 nm) silica particles were studied to investigate the possible mechanism of cytotoxicity and autophagy dysfunction in human bronchial epithelial BEAS-2B cells. The cell viability was decreased in a size-...