TNFα-Induced Necroptosis and Autophagy via Supression of the p38–NF-κB Survival Pathway in L929 Cells

Ye, Yuanchao; Yu, Lu; Wang, Hongju; Tashiro, Shin‐ichi; Onodera, Satoshi; Ikejima, Takashi

doi:10.1254/jphs.11105fp

Cited by 79 publications

(62 citation statements)

References 37 publications

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“…TNF-α can induce autophagy in osteoclasts [121], fibrosarcoma L929 cells [122], and dopaminergic cells [123]. Recently, studies have focused on the association between TNF-α and autophagy in IVD cells.…”

Section: Tnf-α Regulates Autophagymentioning

confidence: 99%

Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration

Wang¹,

Yu²,

Yan³

et al. 2017

ABBS

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Intervertebral disc (IVD) degeneration (IDD) is the most common cause leading to low back pain (LBP), which is a highly prevalent, costly, and crippling condition worldwide. Current treatments for IDD are limited to treat the symptoms and do not target the pathophysiology. Tumor necrosis factor-α (TNF-α) is one of the most potent pro-inflammatory cytokines and signals through its receptors TNFR1 and TNFR2. TNF-α is highly expressed in degenerative IVD tissues, and it is deeply involved in multiple pathological processes of disc degeneration, including matrix destruction, inflammatory responses, apoptosis, autophagy, and cell proliferation. Importantly, anti-TNF-α therapy has shown promise for mitigating disc degeneration and relieving LBP. In this review, following a brief description of TNF-α signal transduction, we mainly focus on the expression pattern and roles of TNF-α in IDD, and summarize the emerging progress regarding its inhibition as a promising biological therapeutic approach to disc degeneration and associated LBP. A better understanding will help to develop novel TNF-α-centered therapeutic interventions for degenerative disc disease.

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Section: Tnf-α Regulates Autophagymentioning

confidence: 99%

Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration

Wang¹,

Yu²,

Yan³

et al. 2017

ABBS

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“…Immunoblot analysis was performed as described previously [19] . npg EDTA, 1.5 mmol/L MgCl 2 , 1 mmol/L DTT, 1 mmol/L PMSF, 1 μg/mL aprotinin, and 1 μg/mL leupeptin).…”

Section: Western Blot Analysismentioning

confidence: 99%

Oridonin induces apoptosis and autophagy in murine fibrosarcoma L929 cells partly via NO-ERK-p53 positive-feedback loop signaling pathway

Wang

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the role of nitric oxide (NO) in oridonin-induced apoptosis and autophagy in murine fibrosarcoma L929 cells and the underlying molecular mechanisms. Methods: Cell viability was measured using MTT assay. Intracellular NO level, SubG 1 cell ratio and autophagy cell ratios were analyzed with flow cytometry after diaminofluorescein-2 diacetate (DAF-2DA), propidium iodide (PI) and monodansylcadaverine (MDC) staining, respec tively. Protein expression was examined using Western blot analysis. Results: Exposure of L929 cells to oridonin (50 µmol/L) for 24 h led to intracellular NO production. Pretreatment with NOS inhibitor 1400w or L-NAME inhibited oridonin-induced apoptosis and autophagy in L929 cells. The pretreatment decreased the apoptosisrelated protein Bax translocation and cytochrome c release, increased Bcl-2 level, reversed the autophagy-associated protein Beclin 1 increase and conversion of LC3 I to LC3 II. Furthermore, pretreatment with NO scavenger DTT completely inhibited oridonin-induced apoptosis and autophagy in L929 cells. In addi tion, oridonin (50 µmol/L) activated ERK and p53 in L929 cells, and the interruption of ERK and p53 activation by PD 98059, pifithrin-α, or ERK siRNA decreased oridonin-induced apoptosis and autophagy. The inhibition of NO production reduced oridonin-induced ERK and p53 activa tion, and NO production was down-regulated by blocking ERK and p53 activation. Conclusion: NO played a pivotal role in oridonin-induced apoptosis and autophagy in L929 cells. Taken together with our previous finding that ERK contributes to p53 activation, it appears that NO, ERK, and p53 form a positive feedback loop. Consequently, we suggest that oridonin-induced apoptosis and autophagy are modulated by the NO-ERK-p53 molecular signaling mechanism in L929 cells.Keywords: oridonin; murine fibrosarcoma L929 cells; apoptosis; autophagy; NO; ERK; p53 Acta Pharmacologica Sinica (2012Sinica ( ) 33: 1055Sinica ( -1061 doi: 10.1038/aps.2012 published online 30 Jul 2012 Original Article is characterized by an ensemble of morphological features, including cellular shrinkage, plasma membrane blebbing, chromatin condensation, nuclear fragmentation and apoptotic body formation [6] . Apoptosis can be triggered by intrinsic and extrinsic pathways that involve either mitochondria or death receptors [7] . Macroautophagy (hereafter referred to as autophagy) is the most active form of autophagy and affects various physiological and pathological processes, including immunity, cancer and neurodegenerative diseases [8,9] . Autophagy is the process by which organelles and cytosolic macromolecules are sequestered into double-membrane structures known as autophagosomes that are subsequently delivered to the lysosome for degradation [10] . Autophagy is regulated by several autophagy-related ATG genes, many of which have mammalian orthologs. Two well-known ATG genes in mammals are Beclin 1 and microtubule-associated . Beclin 1, which is the mammalian homolog of Atg6 and functions in either the autophagic ...

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“…ERK has been shown to induce autophagy in response to a number of anti-tumor agents, such as soyasaponins in colon cancer cells (14). Inhibition of ERK was associated with decrease in autophagy and increase in cellular sensitivity to tumor necrosis factor-α (TNFα) in human breast cancer MCF-7 cells (15). ERK was shown to promote TNFα-induced autophagy in murine fibroblast L929 cells by activating p53 (16).…”

Section: Introductionmentioning

confidence: 99%

Activation of ERK–p53 and ERK-Mediated Phosphorylation of Bcl-2 Are Involved in Autophagic Cell Death Induced by the c-Met Inhibitor SU11274 in Human Lung Cancer A549 Cells

Liu

Yang

et al. 2012

J Pharmacol Sci

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Abstract. SU11274, a small molecule inhibitor of c-Met, was reported to induce apoptosis in human non-small-cell lung cancer (NSCLC) cells. However, SU11274-mediated autophagy in NSCLC cells has rarely been reported. The aim of this study was to elucidate the molecular mechanisms mediating SU11274-induced autophagy in NSCLC A549 cells. Here we reported that SU11274-induced autophagy was accompanied with an increase in the conversion of LC3-I to LC3-II and up-regulation of Beclin-1 expression. Subsequently, we also found that small interfering RNA against c-Met induced A549 cell autophagy while promotion of c-Met by hepatocyte growth factor (HGF) suppressed A549 cell autophagy. Inhibition of autophagy by 3-methyladenine (3-MA) suppressed SU11274-induced cell death, suggesting that SU11274-induced autophagy caused cell death. Further study showed that ERK and p53 were activated after SU11274 treatment. Interruption of ERK and p53 activities decreased SU11274-induced autophagy, and blocking of ERK by the specific inhibitor PD98059 suppressed SU11274-induced p53 activation. Moreover, ERK activation upregulated Beclin-1 expression through induction of Bcl-2 phosphorylation, but p53 did not induce Bcl-2 phosphorylation. In conclusion, inhibition of c-Met induced autophagic cell death, which was associated with ERK-p53 activation and ERK-mediated Bcl-2 phosphorylation in A549 cells.

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TNFα-Induced Necroptosis and Autophagy via Supression of the p38–NF-κB Survival Pathway in L929 Cells

Cited by 79 publications

References 37 publications

Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration

Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration

Oridonin induces apoptosis and autophagy in murine fibrosarcoma L929 cells partly via NO-ERK-p53 positive-feedback loop signaling pathway

Activation of ERK–p53 and ERK-Mediated Phosphorylation of Bcl-2 Are Involved in Autophagic Cell Death Induced by the c-Met Inhibitor SU11274 in Human Lung Cancer A549 Cells

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TNFα-Induced Necroptosis and Autophagy via Supression of the p38–NF-κB Survival Pathway in L929 Cells

Cited by 79 publications

References 37 publications

Tumor necrosis factor-&alpha;: a key contributor to intervertebral disc degeneration

Tumor necrosis factor-&alpha;: a key contributor to intervertebral disc degeneration

Oridonin induces apoptosis and autophagy in murine fibrosarcoma L929 cells partly via NO-ERK-p53 positive-feedback loop signaling pathway

Activation of ERK–p53 and ERK-Mediated Phosphorylation of Bcl-2 Are Involved in Autophagic Cell Death Induced by the c-Met Inhibitor SU11274 in Human Lung Cancer A549 Cells

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Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration

Tumor necrosis factor-α: a key contributor to intervertebral disc degeneration