Suppression of Staphylococcal Enterotoxin B-induced Toxicity by a Nuclear Import Inhibitor

Liu, Danya; Liu, Xue Yan; Robinson, Daniel; Burnett, Christie; Jackson, Charity L.; Seele, Louis; Veach, Ruth Ann; Downs, Sheila; Collins, Robert D.; Ballard, Dean W.; Hawiger, Jacek

doi:10.1074/jbc.m313442200

Cited by 37 publications

(35 citation statements)

References 37 publications

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“…First, previous studies had made only a limited effort to identify hydrophobic sequences with enhanced protein transduction activity (18). Second, despite this limitation, the FGF-4 MTD has been successfully used to deliver biologically active peptides and proteins systemically in animals including dramatic protection to lethal proinflammatory conditions (20,(22)(23)(24). Finally, the hydrophobic MTDs are thought to enter cells directly by penetrating the plasma membrane; (18) in contrast, the basic protein transduction domains bind to the cell surface and bulk entry occurs by endocytosis (25).…”

Section: Discussionmentioning

confidence: 99%

Cell-Permeable NM23 Blocks the Maintenance and Progression of Established Pulmonary Metastasis

et al. 2011

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Occult metastases are a major cause of cancer mortality, even among patients undergoing curative resection. Therefore, practical strategies to target the growth and persistence of already established metastases would provide an important advance in cancer treatment. Here, we assessed the potential of protein therapy using a cell permeable NM23-H1 metastasis suppressor protein. Hydrophobic transduction domains developed from a screen of 1,500 signaling peptide sequences enhanced the uptake of the NM23 protein by cultured cells and systemic delivery to animal tissues. The cell-permeable (CP)-NM23 inhibited metastasis-associated phenotypes in tumor cell lines, blocked the establishment of lung metastases, and cleared already established pulmonary metastases, significantly prolonging the survival of tumor-bearing animals. Therefore, these results establish the potential use of cell-permeable metastasis suppressors as adjuvant therapy against disseminated cancers. Cancer Res; 71(23); 7216-25. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Cell-Permeable NM23 Blocks the Maintenance and Progression of Established Pulmonary Metastasis

et al. 2011

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“…Peptide Synthesis and Purification-cSN50 and SM were synthesized, purified, filter-sterilized, and analyzed as described elsewhere (7,18).…”

Section: Methodsmentioning

confidence: 99%

“…TNF␣ and IL-6 in plasma, monocyte chemoattractant protein 1 (MCP-1) in plasma, and in cultured RAW cell supernatant were measured by a Cytometric Bead Array (BD Biosciences) according to the manufacturer's instructions (7,19).…”

Section: Methodsmentioning

confidence: 99%

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Nuclear Import of Proinflammatory Transcription Factors Is Required for Massive Liver Apoptosis Induced by Bacterial Lipopolysaccharide

Liu¹,

Li²,

Chen³

et al. 2004

Journal of Biological Chemistry

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104

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Stimulation of macrophages with lipopolysaccharide (LPS) leads to the production of cytokines that elicit massive liver apoptosis. We investigated the in vivo role of stress-responsive transcription factors (SRTFs) in this process focusing on the precipitating events that are sensitive to a cell-permeant peptide inhibitor of SRTF nuclear import (cSN50). In the absence of cSN50, mice challenged with LPS displayed very early bursts of inflammatory cytokines/chemokines, tumor necrosis factor ␣ (1 h), interleukin 6 (2 h), interleukin 1 ␤ (2 h), and monocyte chemoattractant protein 1 (2 h). Activation of both initiator caspases 8 and 9 and effector caspase 3 was noted 4 h later when full-blown DNA fragmentation and chromatin condensation were first observed (6 h). At this time an increase of pro-apoptotic Bax gene expression was observed. It was preceded by a decrease of anti-apoptotic Bcl2 and BclX L gene transcripts. Massive apoptosis was accompanied by microvascular injury manifested by hemorrhagic necrosis and a precipitous drop in blood platelets observed at 6 h. An increase in fibrinogen/fibrin degradation products and a rise in plasminogen activator inhibitor 1 occurred between 4 and 6 h. Inhibition of SRTFs nuclear import with the cSN50 peptide abrogated all these changes and increased survival from 7 to 71%. Thus, the nuclear import of SRTFs induced by LPS is a prerequisite for activation of the genetic program that governs cytokines/ chemokines production, liver apoptosis, microvascular injury, and death. These results should facilitate the rational design of drugs that protect the liver from inflammation-driven apoptosis.Programmed cell death (apoptosis) is the major mechanism of embryonic development and remodeling of tissues and organs, homeostatic control of immune cells that recognize self and non-self antigens, and removal of virally infected cells (1). Apoptosis of hepatocytes may occur in fulminant hepatitis, an inflammatory process that is caused by viral and non-viral agents (2). For example, recent gene therapy approaches to correct an inborn error of metabolism led to fulminant liver failure (3). This inflammation-related complication of gene therapy impedes broader application of viral vectors (4, 5). The sequence of intracellular signaling events that underlie inflammation-driven development of ultimately fatal liver apoptosis remains incompletely understood.Fulminant liver apoptosis has been studied in several animal models. These studies indicate that activation of T cells with concanavalin A (6) or with agonists that interact with T cell receptor such as staphylococcal enterotoxin B can lead to massive apoptosis (7,8). Staphylococcal enterotoxin B-induced apoptosis occurs under conditions of metabolic stress imposed by 2-amino-2-deoxy-D-galactosamine (D-Gal).1 Similarly, activation of macrophages with their Toll-like receptors (TLR) agonists, such as lipopolysaccharide (LPS, endotoxin), induces massive liver apoptosis when animals are treated with ethanol or D-Gal (9, 10). By reversibly dep...

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“…In our recent article, we demonstrated that a conjugate of penetratin and the NF-B p50 NLS inhibited NF-B transcriptional activity and thus suppressed the inflammatory response in various in vitro and in vivo inflammatory models (Letoha et al, 2005b). It was wellestablished that intracellular delivery of the NF-B p50 NLS blocks stress-responsive gene expression and inflammation (Torgerson et al, 1998;Yan Liu et al, 2000;Liu et al, 2004); however, penetratin (without any bioactive cargo attached) also proved to be active in the same experimental setting. Our in vitro luciferase gene assays clearly demonstrated that penetratin pretreatment could prevent TNF-or LPS-induced NF-B activation.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and in Vivo Nuclear Factor-κB Inhibitory Effects of the Cell-Penetrating Penetratin Peptide

Letoha¹,

Kúsz²,

Pápai³

et al. 2006

Mol Pharmacol

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Penetratin is a cationic cell-penetrating peptide that has been frequently used for the intracellular delivery of polar bioactive compounds. Recent studies have just revealed the major role of polyanionic membrane proteoglycans and cholesterol-enriched lipid rafts in the uptake of the peptide. Both proteoglycans and lipid-rafts influence inflammatory processes by binding a wide array of proinflammatory mediators; thus, we decided to analyze the effect of penetratin on in vitro and in vivo inflammatory responses. Our in vitro luciferase gene assays demonstrated that penetratin decreased transcriptional activity of nuclear factor-B (NF-B) in tumor necrosis factor (TNF)-stimulated L929 fibroblasts and lipopolysaccharide-activated RAW 264.7 macrophages. Penetratin also inhibited TNF-induced intercellular adhesion molecule-1 expression in human endothelial HMEC-1 cells. Exogenous heparan sulfate abolished the in vitro NF-B inhibitory effects of the peptide. Uptake experiments showed that penetratin was internalized by all of the above-mentioned cell lines in vitro and rapidly entered the cells of the lung and pancreas in vivo. In an in vivo rat model of acute pancreatitis, a disease induced by elevated activities of stress-responsive transcription factors like NF-B, pretreatment with only 2 mg/kg penetratin attenuated the severity of pancreatic inflammation by interfering with IB degradation and subsequent nuclear import of NF-B, inhibiting the expression of proinflammatory genes and improving the monitored laboratory and histological parameters of pancreatitis and associated oxidative stress.

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Suppression of Staphylococcal Enterotoxin B-induced Toxicity by a Nuclear Import Inhibitor

Cited by 37 publications

References 37 publications

Cell-Permeable NM23 Blocks the Maintenance and Progression of Established Pulmonary Metastasis

Cell-Permeable NM23 Blocks the Maintenance and Progression of Established Pulmonary Metastasis

Nuclear Import of Proinflammatory Transcription Factors Is Required for Massive Liver Apoptosis Induced by Bacterial Lipopolysaccharide

In Vitro and in Vivo Nuclear Factor-κB Inhibitory Effects of the Cell-Penetrating Penetratin Peptide

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