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Title: Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice

Abstract

Abstract Traditional methods for carcinogenicity testing rely heavily on the rodent bioassay as the standard for identification of tumorigenic risk. As such, identification of species-specific outcomes and/or metabolism are a frequent argument for regulatory exemption. One example is the association of tumor formation in the mouse lung after exposure to Cyp2F2 ligands. The adverse outcome pathway (AOP) framework offers a theoretical platform to address issues of species specificity that is consistent, transparent, and capable of integrating data from new approach methodologies as well as traditional data streams. A central premise of the AOP concept is that pathway progression from the molecular initiating event (MIE) implies a definable “response-response” (R-R) relationship between each key event (KE) that drives the pathway towards a specific adverse outcome (AO). This article describes an AOP for lung cancer in the mouse from an MIE of Cyp2F2-specific reactive metabolite formation, advancing through KE that include protein and/or nucleic acid adducts, diminished Club Cell 10 kDa (CC10) protein expression, hyperplasia of CC10 deficient Club cells, and culminating in the AO of mixed-cell tumor formation in the distal airways. This tumor formation is independent of route of exposure and our AOP construct is based on overlapping mechanistic events formore » naphthalene, styrene, ethyl benzene, isoniazid, and fluensulfone in the mouse. This AOP is intended to accelerate the explication of an apparent mouse-specific outcome and serve as a starting point for a quantitative analysis of mouse-human differences in susceptibility to the tumorigenic effects of Cyp2F2 ligands.« less

Authors:
 [1]; ORCiD logo [2]
  1. Oak Ridge Institute for Science and Education Fellow at the National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27709
  2. National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27709
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1571840
Resource Type:
Published Article
Journal Name:
Toxicological Sciences
Additional Journal Information:
Journal Name: Toxicological Sciences Journal Volume: 172 Journal Issue: 1; Journal ID: ISSN 1096-6080
Publisher:
Oxford University Press
Country of Publication:
United States
Language:
English

Citation Formats

Hill, III, Thomas, and Conolly, Rory B. Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice. United States: N. p., 2019. Web. doi:10.1093/toxsci/kfz185.
Hill, III, Thomas, & Conolly, Rory B. Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice. United States. doi:10.1093/toxsci/kfz185.
Hill, III, Thomas, and Conolly, Rory B. Mon . "Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice". United States. doi:10.1093/toxsci/kfz185.
@article{osti_1571840,
title = {Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice},
author = {Hill, III, Thomas and Conolly, Rory B.},
abstractNote = {Abstract Traditional methods for carcinogenicity testing rely heavily on the rodent bioassay as the standard for identification of tumorigenic risk. As such, identification of species-specific outcomes and/or metabolism are a frequent argument for regulatory exemption. One example is the association of tumor formation in the mouse lung after exposure to Cyp2F2 ligands. The adverse outcome pathway (AOP) framework offers a theoretical platform to address issues of species specificity that is consistent, transparent, and capable of integrating data from new approach methodologies as well as traditional data streams. A central premise of the AOP concept is that pathway progression from the molecular initiating event (MIE) implies a definable “response-response” (R-R) relationship between each key event (KE) that drives the pathway towards a specific adverse outcome (AO). This article describes an AOP for lung cancer in the mouse from an MIE of Cyp2F2-specific reactive metabolite formation, advancing through KE that include protein and/or nucleic acid adducts, diminished Club Cell 10 kDa (CC10) protein expression, hyperplasia of CC10 deficient Club cells, and culminating in the AO of mixed-cell tumor formation in the distal airways. This tumor formation is independent of route of exposure and our AOP construct is based on overlapping mechanistic events for naphthalene, styrene, ethyl benzene, isoniazid, and fluensulfone in the mouse. This AOP is intended to accelerate the explication of an apparent mouse-specific outcome and serve as a starting point for a quantitative analysis of mouse-human differences in susceptibility to the tumorigenic effects of Cyp2F2 ligands.},
doi = {10.1093/toxsci/kfz185},
journal = {Toxicological Sciences},
number = 1,
volume = 172,
place = {United States},
year = {2019},
month = {8}
}

Journal Article:
Free Publicly Available Full Text
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DOI: 10.1093/toxsci/kfz185

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L.; Kemp, L.</span> </li> <li> Experimental Lung Research, Vol. 13, Issue 1</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.3109/01902148709064309" class="text-muted" target="_blank" rel="noopener noreferrer">10.3109/01902148709064309<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1073/pnas.1319051111" target="_blank" rel="noopener noreferrer" class="name">T helper 17 cells play a critical pathogenic role in lung cancer<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2014-03-31">March 2014</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Chang, S. H.; Mirabolfathinejad, S. G.; Katta, H.</span> </li> <li> Proceedings of the National Academy of Sciences, Vol. 111, Issue 15</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1073/pnas.1319051111" class="text-muted" target="_blank" rel="noopener noreferrer">10.1073/pnas.1319051111<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1093/mutage/ger033" target="_blank" rel="noopener noreferrer" class="name">Styrene exposure and risk of cancer<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2011-07-01">July 2011</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Huff, J.; Infante, P. F.</span> </li> <li> Mutagenesis, Vol. 26, Issue 5</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1093/mutage/ger033" class="text-muted" target="_blank" rel="noopener noreferrer">10.1093/mutage/ger033<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1016/0009-2797(82)90152-1" target="_blank" rel="noopener noreferrer" class="name">Evidence for cytochrome P-450 mediated metabolism in the bronchiolar damage by naphthalene<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="1982-07-01">July 1982</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Warren, D. L.; Brown, D. L.; Buckpitt, A. 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E.; Rucker, R. 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Michael; Jewell, William T.; Fanucchi, Michelle V.</span> </li> <li> Journal of Pharmacology and Experimental Therapeutics, Vol. 309, Issue 1</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1124/jpet.103.062901" class="text-muted" target="_blank" rel="noopener noreferrer">10.1124/jpet.103.062901<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1093/toxsci/kfj001" target="_blank" rel="noopener noreferrer" class="name">Mode of Action in Relevance of Rodent Liver Tumors to Human Cancer Risk<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2005-10-12">October 2005</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Holsapple, Michael P.; Pitot, Henri C.; Cohen, Samuel H.</span> </li> <li> Toxicological Sciences, Vol. 89, Issue 1</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1093/toxsci/kfj001" class="text-muted" target="_blank" rel="noopener noreferrer">10.1093/toxsci/kfj001<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1021/ci0600915" target="_blank" rel="noopener noreferrer" class="name">QSAR Modeling of in Vitro Inhibition of Cytochrome P450 3A4*<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2006-08-17">August 2006</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Mao, Boryeu; Gozalbes, Rafael; Barbosa, Frédérique</span> </li> <li> Journal of Chemical Information and Modeling, Vol. 46, Issue 5</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1021/ci0600915" class="text-muted" target="_blank" rel="noopener noreferrer">10.1021/ci0600915<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> <div> <h2 class="title" style="margin-bottom:0;" data-apporder=""> <a href="https://doi.org/10.1289/EHP1304" target="_blank" rel="noopener noreferrer" class="name">Application of Adverse Outcome Pathways to U.S. EPA’s Endocrine Disruptor Screening Program<span class="fa fa-external-link" aria-hidden="true"></span></a> <small class="text-muted" style="text-transform:uppercase; font-size:0.75rem;"><br/> <span class="type">journal</span>, <span class="date" data-date="2017-09-22">September 2017</span></small> </h2> <ul class="small references-list" style="list-style-type:none; margin-top: 0.5em; padding-left: 0; line-height:1.8em;"> <li> <span style="color:#5C7B2D;"> Browne, Patience; Noyes, Pamela D.; Casey, Warren M.</span> </li> <li> Environmental Health Perspectives, Vol. 125, Issue 9</li> <li> <span class="text-muted related-url">DOI: <a href="https://doi.org/10.1289/EHP1304" class="text-muted" target="_blank" rel="noopener noreferrer">10.1289/EHP1304<span class="fa fa-external-link" aria-hidden="true"></span></a></span> </li> </ul> <hr/> </div> </div> <div class="pagination-container small"> <a class="pure-button prev page" href="#" rel="prev"><span class="fa fa-angle-left"></span></a><ul class="pagination d-inline-block" style="padding-left:.2em;"></ul><a class="pure-button next page" href="#" rel="next"><span class="fa fa-angle-right"></span></a> </div> </div> </div> <div class="col-sm-3 order-sm-3"> <ul class="nav nav-stacked"> <li class="active"><a href="" class="reference-type-filter tab-nav" data-tab="biblio-references" data-filter="type" data-pattern="*"><span class="fa fa-angle-right"></span> All References</a></li> <li class="small" style="margin-left:.75em; 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float:none;">[ × clear filter / sort ]</a> </div> </form> </div> </div> </div> </section> <section id="biblio-related" class="tab-content tab-content-sec " data-tab="biblio"> <div class="row"> <div class="col-sm-9 order-sm-9"> <section id="biblio-similar" class="tab-content tab-content-sec active" data-tab="related"> <div class="padding"> <p class="lead text-muted" style="font-size: 18px; margin-top:0px;">Similar Records in DOE PAGES and OSTI.GOV collections:</p> <aside> <ul class="item-list" itemscope itemtype="http://schema.org/ItemList" style="padding-left:0; list-style-type: none;"> <li> <div class="article item document" itemprop="itemListElement" itemscope itemtype="http://schema.org/WebPage"><meta itemprop="position" content="0" /><div class="item-info"> <h2 class="title" itemprop="name headline"><a href="/biblio/1015519-defining-modeling-known-adverse-outcome-pathways-domoic-acid-neuronal-signaling-case-study" itemprop="url">Defining and Modeling Known Adverse Outcome Pathways: Domoic Acid and Neuronal Signaling as a Case Study</a></h2> <div class="metadata"> <small class="text-muted" style="text-transform:uppercase;display:block;line-height:2.5em;">Journal Article</small><span class="authors"> <span class="author">Watanabe, Karen H</span> ; <span class="author">Andersen, Melvin E</span> ; <span class="author">Basu, Nil</span> ; <span class="author">...</span> <span class="text-muted pubdata"> - Environmental Toxicology and Chemistry, 30(1):9-21</span> </span> </div> <div class="abstract">An adverse outcome pathway (AOP) is a sequence of key events from a molecular-level initiating event and an ensuing cascade of steps to an adverse outcome with population level significance. To implement a predictive strategy for ecotoxicology, the multiscale nature of an AOP requires computational models to link salient processes (e.g., in chemical uptake, toxicokinetics, toxicodynamics, and population dynamics). A case study with domoic acid was used to demonstrate strategies and enable generic recommendations for developing computational models in an effort to move toward a toxicity testing paradigm focused on toxicity pathway perturbations applicable to ecological risk assessment. Domoic acid,<a href='#' onclick='$(this).hide().next().show().next().show();return false;' style='margin-left:10px;'>more »</a><span style='display:none;'> an algal toxin with adverse effects on both wildlife and humans, is a potent agonist for kainate receptors (ionotropic glutamate receptors whose activation leads to the influx of Na+ and Ca2+). Increased Ca2+ concentrations result in neuronal excitotoxicity and cell death primarily in the hippocampus, which produces seizures, impairs learning and memory, and alters behavior in some species. Altered neuronal Ca2+ is a key process in domoic acid toxicity which can be evaluated in vitro. Further, results of these assays would be amenable to mechanistic modeling for identifying domoic acid concentrations and Ca2+ perturbations that are normal, adaptive, or clearly toxic. In vitro assays with outputs amenable to measurement in exposed populations can link in vitro to in vivo conditions, and toxicokinetic information will aid in linking in vitro results to the individual organism. Development of an AOP required an iterative process with three important outcomes: (1) a critically reviewed, stressor-specific AOP; (2) identification of key processes suitable for evaluation with in vitro assays; and (3) strategies for model development.</span><a href='#' onclick='$(this).hide().prev().hide().prev().show();return false;' style='margin-left:10px;display:none;'>« less</a></div><div class="metadata-links small clearfix text-muted" style="margin-top:15px;"> <div class="pure-menu pure-menu-horizontal pull-right" style="width:unset;"> <ul class="pure-menu-list"> <li class="pure-menu-item"><span class="item-info-ftlink">DOI: <a class="misc doi-link " href="https://doi.org/10.1002/etc.373" target="_blank" rel="noopener" title="Link to document DOI" data-ostiid="1015519" data-product-type="Journal Article" data-product-subtype="AC" >10.1002/etc.373</a></span></li> </ul> </div> </div> </div> <div class="clearfix"></div> </div> </li> <li> <div class="article item document" itemprop="itemListElement" itemscope itemtype="http://schema.org/WebPage"><meta itemprop="position" content="1" /><div class="item-info"> <h2 class="title" itemprop="name headline"><a href="/pages/biblio/1660491-gene-expression-thresholds-derived-from-short-term-exposures-identify-rat-liver-tumorigens" itemprop="url">Gene Expression Thresholds Derived From Short-term Exposures Identify Rat Liver Tumorigens</a></h2> <div class="metadata"> <small class="text-muted" style="text-transform:uppercase;display:block;line-height:2.5em;">Journal Article</small><span class="authors"> <span class="author">Hill, III,, Thomas</span> ; <span class="author">Rooney, John</span> ; <span class="author">Abedini, Jaleh</span> ; <span class="author">...</span> <span class="text-muted pubdata"> - Toxicological Sciences</span> </span> </div> <div class="abstract">Abstract Traditional methods for cancer risk assessment are resource-intensive, retrospective, and not feasible for the vast majority of environmental chemicals. In this study, we investigated whether quantitative genomic data from short-term studies may be used to set protective thresholds for potential tumorigenic effects. We hypothesized that gene expression biomarkers measuring activation of the key early events in established pathways for rodent liver cancer exhibit cross-chemical thresholds for tumorigenesis predictive for liver cancer risk. We defined biomarker thresholds for 6 major liver cancer pathways using training sets of chemicals with short-term genomic data (3–29 days of exposure) from the TG-GATES (n = 77 chemicals)<a href='#' onclick='$(this).hide().next().show().next().show();return false;' style='margin-left:10px;'>more »</a><span style='display:none;'> and DrugMatrix (n = 86 chemicals) databases and then tested these thresholds within and between datasets. The 6 pathway biomarkers represented genotoxicity, cytotoxicity, and activation of xenobiotic, steroid, and lipid receptors (aryl hydrocarbon receptor, constitutive activated receptor, estrogen receptor, and peroxisome proliferator-activated receptor α). Thresholds were calculated as the maximum values derived from exposures without detectable liver tumor outcomes. We identified clear response values that were consistent across training and test sets. Thresholds derived from the TG-GATES training set were highly predictive (97%) in a test set of independent chemicals, whereas thresholds derived from the DrugMatrix study were 96%–97% predictive for the TG-GATES study. Threshold values derived from an abridged gene list (2/biomarker) also exhibited high predictive accuracy (91%–94%). These findings support the idea that early genomic changes can be used to establish threshold estimates or “molecular tipping points” that are predictive of later-life health outcomes.</span><a href='#' onclick='$(this).hide().prev().hide().prev().show();return false;' style='margin-left:10px;display:none;'>« less</a></div><div class="metadata-links small clearfix text-muted" style="margin-top:15px;"> <div class="pure-menu pure-menu-horizontal pull-right" style="width:unset;"> <ul class="pure-menu-list"> <li class="pure-menu-item"><span class="item-info-ftlink">DOI: <a class="misc doi-link " href="https://doi.org/10.1093/toxsci/kfaa102" target="_blank" rel="noopener" title="Link to document DOI" data-ostiid="1660491" data-product-type="Journal Article" data-product-subtype="PA" >10.1093/toxsci/kfaa102</a></span></li> </ul> </div> </div> </div> <div class="clearfix"></div> </div> </li> <li> <div class="article item document" itemprop="itemListElement" itemscope itemtype="http://schema.org/WebPage"><meta itemprop="position" content="2" /><div class="item-info"> <h2 class="title" itemprop="name headline"><a href="/biblio/1019194-reverse-engineering-adverse-outcome-pathways" itemprop="url">Reverse Engineering Adverse Outcome Pathways</a></h2> <div class="metadata"> <small class="text-muted" style="text-transform:uppercase;display:block;line-height:2.5em;">Journal Article</small><span class="authors"> <span class="author">Perkins, Edward</span> ; <span class="author">Chipman, J K</span> ; <span class="author">Edwards, Stephen</span> ; <span class="author">...</span> <span class="text-muted pubdata"> - Environmental Toxicology and Chemistry, 30(1):22-38</span> </span> </div> <div class="abstract">The toxicological effects of many stressors are mediated through unknown, or poorly characterized, mechanisms of action. We describe the application of reverse engineering complex interaction networks from high dimensional omics data (gene, protein, metabolic, signaling) to characterize adverse outcome pathways (AOPs) for chemicals that disrupt the hypothalamus-pituitary-gonadal endocrine axis in fathead minnows. Gene expression changes in fathead minnow ovaries in response to 7 different chemicals, over different times, doses, and in vivo versus in vitro conditions were captured in a large data set of 868 arrays. We examined potential AOPs of the antiandrogen flutamide using two mutual information theory methods,<a href='#' onclick='$(this).hide().next().show().next().show();return false;' style='margin-left:10px;'>more »</a><span style='display:none;'> ARACNE and CLR to infer gene regulatory networks and potential adverse outcome pathways. Representative networks from these studies were used to predict a network path from stressor to adverse outcome as a candidate AOP. The relationship of individual chemicals to an adverse outcome can be determined by following perturbations through the network in response to chemical treatment leading to the nodes associated with the adverse outcome. Identification of candidate pathways allows for formation of testable hypotheses about key biologic processes, biomarkers or alternative endpoints, which could be used to monitor an adverse outcome pathway. Finally, we identify the unique challenges facing the application of this approach in ecotoxicology, and attempt to provide a road map for the utilization of these tools. Key Words: mechanism of action, toxicology, microarray, network inference</span><a href='#' onclick='$(this).hide().prev().hide().prev().show();return false;' style='margin-left:10px;display:none;'>« less</a></div><div class="metadata-links small clearfix text-muted" style="margin-top:15px;"> <div class="pure-menu pure-menu-horizontal pull-right" style="width:unset;"> <ul class="pure-menu-list"> <li class="pure-menu-item"><span class="item-info-ftlink">DOI: <a class="misc doi-link " href="https://doi.org/10.1002/etc.374" target="_blank" rel="noopener" title="Link to document DOI" data-ostiid="1019194" data-product-type="Journal Article" data-product-subtype="AC" >10.1002/etc.374</a></span></li> </ul> </div> </div> </div> <div class="clearfix"></div> </div> </li> <li> <div class="article item document" itemprop="itemListElement" itemscope itemtype="http://schema.org/WebPage"><meta itemprop="position" content="3" /><div class="item-info"> <h2 class="title" itemprop="name headline"><a href="/biblio/22239623-rapamycin-targeting-mtor-hedgehog-signaling-pathways-blocks-human-rhabdomyosarcoma-growth-xenograft-murine-model" itemprop="url">Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model</a></h2> <div class="metadata"> <small class="text-muted" style="text-transform:uppercase;display:block;line-height:2.5em;">Journal Article</small><span class="authors"> <span class="author">Kaylani, Samer Z.</span> ; <span class="author">Xu, Jianmin</span> ; <span class="author">Srivastava, Ritesh K.</span> ; <span class="author">...</span> <span class="text-muted pubdata"> - Biochemical and Biophysical Research Communications</span> </span> </div> <div class="abstract">Graphical abstract: Intervention of poorly differentiated RMS by rapamycin: In poorly differentiated RMS, rapamycin blocks mTOR and Hh signaling pathways concomitantly. This leads to dampening in cell cycle regulation and induction of apoptosis. This study provides a rationale for the therapeutic intervention of poorly differentiated RMS by treating patients with rapamycin alone or in combination with other chemotherapeutic agents. -- Highlights: •Rapamycin abrogates RMS tumor growth by modulating proliferation and apoptosis. •Co-targeting mTOR/Hh pathways underlie the molecular basis of effectiveness. •Reduction in mTOR/Hh pathways diminish EMT leading to reduced invasiveness. -- Abstract: Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue<a href='#' onclick='$(this).hide().next().show().next().show();return false;' style='margin-left:10px;'>more »</a><span style='display:none;'> sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis. Interestingly, the mechanism by which rapamycin diminished RMS tumor growth involved simultaneous inhibition of mTOR and hedgehog (Hh) pathways. Diminution in these pathways in this model of RMS also inhibited epithelial mesenchymal transition (EMT) which then dampened the invasiveness of these tumors. Our data provide bases for using rapamycin either alone or in combination with traditional chemotherapeutic drugs to block the pathogenesis of high risk RMS.</span><a href='#' onclick='$(this).hide().prev().hide().prev().show();return false;' style='margin-left:10px;display:none;'>« less</a></div><div class="metadata-links small clearfix text-muted" style="margin-top:15px;"> <div class="pure-menu pure-menu-horizontal pull-right" style="width:unset;"> <ul class="pure-menu-list"> <li class="pure-menu-item"><span class="item-info-ftlink">DOI: <a class="misc doi-link " href="https://doi.org/10.1016/J.BBRC.2013.05.001" target="_blank" rel="noopener" title="Link to document DOI" data-ostiid="22239623" data-product-type="Journal Article" data-product-subtype="AC" >10.1016/J.BBRC.2013.05.001</a></span></li> </ul> </div> </div> </div> <div class="clearfix"></div> </div> </li> <li> <div class="article item document" itemprop="itemListElement" itemscope itemtype="http://schema.org/WebPage"><meta itemprop="position" content="4" /><div class="item-info"> <h2 class="title" itemprop="name headline"><a href="/biblio/22285374-reactive-oxygen-species-mediate-cr-vi-induced-carcinogenesis-through-pi3k-akt-dependent-activation-gsk-catenin-signaling" itemprop="url">Reactive oxygen species mediate Cr(VI)-induced carcinogenesis through PI3K/AKT-dependent activation of GSK-3β/β-catenin signaling</a></h2> <div class="metadata"> <small class="text-muted" style="text-transform:uppercase;display:block;line-height:2.5em;">Journal Article</small><span class="authors"> <span class="author">Son, Young-Ok</span> ; <span class="author">Pratheeshkumar, Poyil</span> ; <span class="author">Wang, Lei</span> ; <span class="author">...</span> <span class="text-muted pubdata"> - Toxicology and Applied Pharmacology</span> </span> </div> <div class="abstract">Cr(VI) compounds are known human carcinogens that primarily target the lungs. Cr(VI) produces reactive oxygen species (ROS), but the exact effects of ROS on the signaling molecules involved in Cr(VI)-induced carcinogenesis have not been extensively studied. Chronic exposure of human bronchial epithelial cells to Cr(VI) at nanomolar concentrations (10–100 nM) for 3 months not only induced cell transformation, but also increased the potential of these cells to invade and migrate. Injection of Cr(VI)-stimulated cells into nude mice resulted in the formation of tumors. Chronic exposure to Cr(VI) increased levels of intracellular ROS and antiapoptotic proteins. Transfection with catalase or superoxide<a href='#' onclick='$(this).hide().next().show().next().show();return false;' style='margin-left:10px;'>more »</a><span style='display:none;'> dismutase (SOD) prevented Cr(VI)-mediated increases in colony formation, cell invasion, migration, and xenograft tumors. While chronic Cr(VI) exposure led to activation of signaling cascades involving PI3K/AKT/GSK-3β/β-catenin and PI3K/AKT/mTOR, transfection with catalase or SOD markedly inhibited Cr(VI)-mediated activation of these signaling proteins. Inhibitors specific for AKT or β-catenin almost completely suppressed the Cr(VI)-mediated increase in total and active β-catenin proteins and colony formation. In particular, Cr(VI) suppressed autophagy of epithelial cells under nutrition deprivation. Furthermore, there was a marked induction of AKT, GSK-3β, β-catenin, mTOR, and carcinogenic markers in tumor tissues formed in mice after injection with Cr(VI)-stimulated cells. Collectively, our findings suggest that ROS is a key mediator of Cr(VI)-induced carcinogenesis through the activation of PI3K/AKT-dependent GSK-3β/β-catenin signaling and the promotion of cell survival mechanisms via the inhibition of apoptosis and autophagy. - Highlights: • Chronic exposure to Cr(VI) induces carcinogenic properties in BEAS-2B cells. • ROS play an important role in Cr(VI)-induced tumorigenicity of BEAS-2B cells. • PI3K/AKT/GSK-3β/β-catenin signaling involved in Cr(VI) carcinogenesis. • The inhibition of apoptosis and autophagy contributes to Cr(VI) carcinogenesis.</span><a href='#' onclick='$(this).hide().prev().hide().prev().show();return false;' style='margin-left:10px;display:none;'>« less</a></div><div class="metadata-links small clearfix text-muted" style="margin-top:15px;"> <div class="pure-menu pure-menu-horizontal pull-right" style="width:unset;"> <ul class="pure-menu-list"> <li class="pure-menu-item"><span class="item-info-ftlink">DOI: <a class="misc doi-link " href="https://doi.org/10.1016/J.TAAP.2013.04.036" target="_blank" rel="noopener" title="Link to document DOI" data-ostiid="22285374" data-product-type="Journal Article" data-product-subtype="AC" >10.1016/J.TAAP.2013.04.036</a></span></li> </ul> </div> </div> </div> <div class="clearfix"></div> </div> </li> </ul> </aside> </div> </section> </div> <div class="col-sm-3 order-sm-3"> <ul class="nav nav-stacked"> <li class="active"><a class="tab-nav disabled" data-tab="related" style="color: #636c72 !important; opacity: 1;"><span class="fa fa-angle-right"></span> Similar Records</a></li> </ul> </div> </div> </section> </div></div> </div> </div> </section> <footer class="" style="background-color:#f9f9f9; /* padding-top: 0.5rem; */"> <div class="footer-minor"> <div class="container"> <hr class="footer-separator" /> <div class="text-center" style="margin-top:1.25rem;"> <div class="pure-menu pure-menu-horizontal"> <ul class="pure-menu-list" id="footer-org-menu"> <li class="pure-menu-item"> <a href="https://energy.gov" target="_blank" rel="noopener noreferrer"> <img src="data:image/gif;base64,R0lGODlhAQABAIAAAP///wAAACH5BAEAAAAALAAAAAABAAEAAAICRAEAOw==" class="sprite sprite-footer-us-doe-min" alt="U.S. Department of Energy" /> </a> </li> <li class="pure-menu-item"> <a href="https://www.energy.gov/science/office-science" target="_blank" rel="noopener noreferrer"> <img src="data:image/gif;base64,R0lGODlhAQABAIAAAP///wAAACH5BAEAAAAALAAAAAABAAEAAAICRAEAOw==" class="sprite sprite-footer-office-of-science-min" alt="Office of Science" /> </a> </li> <li class="pure-menu-item"> <a href="/"> <img src="data:image/gif;base64,R0lGODlhAQABAIAAAP///wAAACH5BAEAAAAALAAAAAABAAEAAAICRAEAOw==" class="sprite sprite-footer-osti-min" alt="Office of Scientific and Technical Information" /> </a> </li> </ul> </div> </div> <div class="text-center small" style="margin-top:0.5em;margin-bottom:2.0rem;"> <div class="pure-menu pure-menu-horizontal"> <ul class="pure-menu-list"> <li class="pure-menu-item"><a href="/disclaim" class="pure-menu-link"><span class="fa fa-institution"></span> Website Policies <span class="hidden-xs">/ Important Links</span></a></li> <li class="pure-menu-item"><a href="/pages/contact" class="pure-menu-link"><span class="fa fa-comments-o"></span> Contact Us</a></li> <li class="d-block d-md-none"></li> <li class="pure-menu-item"><a href="https://www.facebook.com/ostigov" target="_blank" rel="noopener noreferrer" class="pure-menu-link social"><span class="fa fa-facebook" style=""></span></a></li> <li class="pure-menu-item"><a href="https://twitter.com/OSTIgov" target="_blank" rel="noopener noreferrer" class="pure-menu-link social"><span class="fa fa-twitter" style=""></span></a></li> <li class="pure-menu-item"><a href="https://www.youtube.com/user/ostigov" target="_blank" rel="noopener noreferrer" class="pure-menu-link social"><span class="fa fa-youtube-play" style=""></span></a></li> </ul> </div> </div> </div> </div> </footer> <link href="/pages/css/pages.fonts.200912.1307.css" rel="stylesheet"> <script src="/pages/js/pages.200912.1307.js"></script><noscript></noscript> <script defer src="/pages/js/pages.biblio.200912.1307.js"></script><noscript></noscript> <script defer src="/pages/js/lity.js"></script><noscript></noscript> <script async type="text/javascript" src="/pages/js/Universal-Federated-Analytics-Min.js?agency=DOE" id="_fed_an_ua_tag"></script><noscript></noscript> </body> <!-- DOE PAGES v.200912.1307 --> </html>