Defective stress kinase and Bak activation in response to ionizing radiation but not cisplatin in a non-small cell lung carcinoma cell line

Viktorsson, Kristina; Ekedahl, Jessica; Lindebro, Maria C; Lewensohn, Rolf; Zhivotovsky, Boris; Linder, Stig; Shoshan, Maria C.

doi:10.1016/s0014-4827(03)00264-7

Cited by 35 publications

(35 citation statements)

References 31 publications

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“…increased induction of apoptosis (6,14,16,18,19). Moreover the DNA damageinduced apoptotic response has been found to be reduced in JNK-deficient cells, in cells expressing a kinase-dead JNK mutant, and in cells treated with SP600125, a pharmacological inhibitor of JNK (6,17,19). In agreement with this, we have shown that impaired activation of JNK is involved in resistance to low LET IR in NSCLC cells (6).…”

supporting

confidence: 82%

“…However, high LET IR (accelerated ions) has recently been suggested to be therapeutically superior because of its physical as well as biological properties (1,2). A large fraction of tumors show resistance to low LET IR by mechanisms that are only partly elucidated (3)(4)(5)(6)(7). Non-small cell lung carcinoma (NSCLC) is one example of such a resistance-prone tumor type (4,5).…”

mentioning

confidence: 99%

“…We have previously shown that insufficient activation of mitochondria may play a role in the impaired apoptotic signaling observed in response to low LET photon IR in NSCLC cell lines. This lack of apoptotic signaling may contribute to the emergence of an intrinsic radioresistant phenotype of NSCLC (4,6).…”

mentioning

confidence: 99%

“…Activation of the SAPK JNK in response to DNA damage is mainly associated with increased cell death, i.e. increased induction of apoptosis (6,14,16,18,19). Moreover the DNA damageinduced apoptotic response has been found to be reduced in JNK-deficient cells, in cells expressing a kinase-dead JNK mutant, and in cells treated with SP600125, a pharmacological inhibitor of JNK (6,17,19).…”

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confidence: 99%

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Proteomics and Pathway Analysis Identifies JNK Signaling as Critical for High Linear Energy Transfer Radiation-induced Apoptosis in Non-small Lung Cancer Cells

Ståhl

Fung

Adams

et al. 2009

Molecular & Cellular Proteomics

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During the past decade, we have witnessed an explosive increase in generation of large proteomics data sets, not least in cancer research. There is a growing need to extract and correctly interpret information from such data sets to generate biologically relevant hypotheses. A pathway search engine (PSE) has recently been developed as a novel tool intended to meet these requirements. Ionizing radiation (IR) is an anticancer treatment modality that triggers multiple signal transduction networks. In this work, we show that high linear energy transfer (LET) IR induces apoptosis in a non-small cell lung cancer cell line, U-1810, whereas low LET IR does not. PSE was applied to study changes in pathway status between high and low LET IR to find pathway candidates of importance for high LET-induced apoptosis. Such pathways are potential clinical targets, and they were further validated in vitro. We used an unsupervised shotgun proteomics approach where high resolution mass spectrometry coupled to nanoflow liquid chromatography determined the identity and relative abundance of expressed proteins. Based on the proteomics data, PSE suggested the JNK pathway (p ‫؍‬ 6⅐10 ؊6 ) as a key event in response to high LET IR. In addition, the Fas pathway was found to be activated (p ‫؍‬ 3⅐10 ؊5 ) and the p38 pathway was found to be deactivated (p ‫؍‬ 0.001) compared with untreated cells. Antibodybased analyses confirmed that high LET IR caused an increase in phosphorylation of JNK. Moreover pharmacological inhibition of JNK blocked high LET-induced apoptotic signaling. In contrast, neither an activation of p38 nor a role for p38 in high LET IR-induced apoptotic signaling was found. We conclude that, in contrast to conventional low LET IR, high LET IR can trigger activation of the JNK pathway, which in turn is critical for induction of apoptosis in these cells. Thus PSE predictions were largely confirmed, and PSE was proven to be a useful hypothesis-generating tool.

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confidence: 82%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Proteomics and Pathway Analysis Identifies JNK Signaling as Critical for High Linear Energy Transfer Radiation-induced Apoptosis in Non-small Lung Cancer Cells

Ståhl

Fung

Adams

et al. 2009

Molecular & Cellular Proteomics

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“…Flow Cytometric Analysis of Bax Activation-Bax-associated conformational changes were assessed as previously described (17). Briefly, after fixation (0.25% paraformaldehyde, 5 min) and washing, cells were incubated for 30 min in the presence of digitonin (100 g/ml) with antibodies recognizing NH 2 -terminal epitopes of Bax (clone 6A7; BD Pharmingen).…”

Section: Methodsmentioning

confidence: 99%

Full-length p73α Represses Drug-induced Apoptosis in Small Cell Lung Carcinoma Cells

Nyman

Sobczak-Pluta

Vlachos

et al. 2005

Journal of Biological Chemistry

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The p73 gene, a member of the p53 family, encodes several variants through differential splicing and use of alternative promoters. At the NH 2 terminus, two different promoters generate the fulllength and the ⌬N isoforms, with or without the transactivating domain. At the COOH terminus, seven isoforms generated through alternative splicing have been cloned. Previous studies have demonstrated that ⌬Np73 isoforms exert a dominant-negative effect on p73 by blocking their transactivation activity and hence the ability to induce apoptosis. Considerable efforts are made to identify the functional diversity of the COOH-terminal p73 variants. In this study, we found that p73␣ inhibited drug-induced apoptosis in small cell lung carcinoma cells, whereas p73␤ promoted it. p73␣ prevented Bax activation, mitochondrial dysfunction, and caspase activation. In addition, p73␣ was also able to reduce apoptosis induced by the BH3-only protein PUMA (p53 up-regulated modulator of apoptosis). Furthermore, we discovered that p73␣ is able to inhibit the pro-apoptotic effect of p73␤, demonstrating the existence of equilibrium between these two p73 isoforms. In conclusion, the reported overexpression of p73␣ in certain tumor types, and our findings that p73␣ exerts anti-apoptotic functions, indicate a potential oncogenic activity for p73.

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Protective effect of metoclopramide against organophosphate‐induced apoptosis in the murine skin fibroblast L929

Jaber

Petroianu

Rizvi

et al. 2017

J of Applied Toxicology

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This study was performed to evaluate the protective efficacy of metoclopramide (MCP) against the organophosphates paraoxon (POX)- and malathion (MLT)-induced apoptosis in the murine L929 skin fibroblasts. L929 cells were exposed to either POX (10 nm) or 1.0 μm MLT in the absence and presence of increased concentrations of MCP. The protective effect of MCP on these organophosphate-stimulated apoptotic events was evaluated by flow cytometry analysis after staining with annexin-V/propidium iodide, processing and activation of the executioner caspase-3, cleavage of the poly-ADP ribose polymerase, fragmentation of the nucleosomal DNA and disruption of the mitochondrial membrane potential (Δψ). Our results showed that increased doses of MCP alone (≥10 μm) did not induce apoptosis or activation of caspase-3. Pretreatment of the cells with MCP attenuated all the apoptotic events triggered by the organophosphate compounds in a dose-dependent manner reaching ~70-80% protection when they were preincubated at 1 and 5 μm of the drug before the addition of POX and MLT, respectively. Interestingly, MCP did not offer a significant protective effect against the cytotoxicity of tumor necrosis factor-α, cisplatinum, etoposide or paclitaxel, which stimulate apoptosis by various mechanisms, suggesting that the anti-apoptotic effect of the drug is specific to organophosphates. The strong and specific anti-apoptotic activity of subclinical doses of MCP against the cytotoxicity of organophosphate compounds suggests its potential clinical application in treating their poisoning.

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Defective stress kinase and Bak activation in response to ionizing radiation but not cisplatin in a non-small cell lung carcinoma cell line

Cited by 35 publications

References 31 publications

Proteomics and Pathway Analysis Identifies JNK Signaling as Critical for High Linear Energy Transfer Radiation-induced Apoptosis in Non-small Lung Cancer Cells

Proteomics and Pathway Analysis Identifies JNK Signaling as Critical for High Linear Energy Transfer Radiation-induced Apoptosis in Non-small Lung Cancer Cells

Full-length p73α Represses Drug-induced Apoptosis in Small Cell Lung Carcinoma Cells

Protective effect of metoclopramide against organophosphate‐induced apoptosis in the murine skin fibroblast L929

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