Abstract 2579: YK5, a small molecule inhibitor of Hsp70 and Hsc70, reveals a multifaceted role for the Hsp70 chaperones in regulating oncogenic and non-oncogenic addiction of tumors
Anna RodinaYanlong KangTony TaldoneHardik PatelPallav D. PatelEloisi Caldas-LopesHediye Erdjument‐BromageMónica L. GuzmánJason C. YoungAri MelnickGabriela Chiosis
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Abstract Background. The cancerous phenotype evolves through accumulation of a large repertoire of elements that allow for increased proliferative potential, self-sufficiency in growth signals and resistance to apoptotic and antiproliferative signals. While much is now gained in understanding the many factors that lead to a malignant phenotype, little remains known on how cancer cells are able to accumulate and to survive with such complexity and high load of aberrant processes. Study design. Here we use the novel dual Hsp70 and Hsc70 inhibitor, YK5, and its biotinylated derivative, YK55, to investigate the interactome of cytosolic Hsp70s. Results. We show that heat shock protein 70 family members (Hsp70s) keep active conformations of key oncoproteins and inhibit the function of tumor suppressors. Hsp70s also buffer levels of activated molecules by maintaining them in a conformation that alters their dephosphorylation by phosphatases. Pharmacologic inhibition of Hsp70s by YK5 impairs oncoprotein stability and function, restores tumor suppressor activity, affects major cancer hallmarks and is selectively lethal to cancer cells. We show that enhanced affinity of YK5 for cancer cell-Hsp70s species is an essential mechanism for providing selective tumor lethality. Conclusion. By demonstrating that pharmacologic dual inhibitors of Hsp70 and Hsc70, such as YK5, confer specific and broad tumor lethality, and interact selectively with tumor Hsp70s species, this work proposes Hsp70s inhibitors as potential anti-cancer therapeutics with a large spectrum of activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2579. doi:10.1158/1538-7445.AM2011-2579Keywords:
Dephosphorylation
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Heat shock proteins (HSPs) are remarkably conserved in all living organisms. The upregulation of expression of HSPs is triggered by a variety of physiological and environmental insults. HSPs play an important role in protecting against protein denaturation and subsequent celluar stress, which damages the intestinal mucosa and reduces the protective function of the mucosal barrier, resulting in the formation of stress ulcers. Heat shock protein 70 (HSP70) is the most widely studied of all HSPs and has numerous important chaperoning functions. Stress accelerates the synthesis of HSP70, which in turn inhibits the apoptosis of intestinal mucosal cells. In this article, we review the main classification of HSPs, the expression and regulation of HSPs and their roles in stress ulcers. We also discuss the role of functional amino acids in regulating the expression of HSPs (particularly HSP70) and protecting the intestinal mucosa and other tissues.
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The treatment of either elemene (50 #mu#g/ml, 1h) or heat shock (42deg C, 1h) could increase the membrane expression of HSP70, ActD had a synergistic action with both treatments. HSP70EP (Enhancer protein) gene was up-regulated and HSPA2 gene was down-regulated in both treatments. HSF1 gene was up-regulated in heat shock treatment but down-regulated in elemene treatment. The genes closely correlated with tumor immune, such as HSP70, HSP72, HSP75, HSP90 and gp96 were not changed. Comparing with heat shock treatment, elemene can cause a higher percentn of HSP70 membrane expression in HepG2 cells and that may be caused by its altering the distribution of the already existing HSP70 and/or accelerating the HSP70 mRNA translation. Both treatments can change the expression of genes associated with the transcription control factors of HSPs and decrease HSPA2 gene expression.
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Objective:To study the influnence of elemene or heat shock treatment upon the expression of membrane HSP70 and HSPs genes in HepG 2 cells.Methods:HSP70 expression was observed by immunofluorescence and FCM techniques.HSP70 gene transcription was blocked by ActD.Genechip was used to study the expression of HSPs genes and the genes associated with the control of HSPs transcription.Results:The treatment of either elemene(50 μg/ml,1 h) or heat shock(42℃,1 h)could increase the membrane expression of HSP70,ActD had a synergistic action with both treatments.HSP70EP(Enhancer Protein) gene was up regulated and HSPA2 gene was down regulated in both treatments.HSF1 gene was up regulated in heat shock treatment but down regulated in elemene treatment.The genes closely correlated with tumor immune,such as HSP70,HSP72,HSP75,HSP90 and gp96 were not changed.Conclusion:Comparing with heat shock treatment,elemene can cause a higher percent of HSP70 membrane expression in HepG 2 cells and that may be caused by its altering the distribution of the already existing HSP70 and/or accelerating the HSP70 mRNA translation.Both treatments can change the expression of genes associated with the transcription control factors of HSPs and decrease HSPA2 gene expression.
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Abstract Heat shock proteins (Hsps) are a ubiquitous feature of cells in which these proteins cope with stress‐induced denaturation of other proteins. Among the different families of Hsps, the 70 kDa family ( hsp70 ) is the most highly conserved and has been most extensively studied. Apart from their primary role in cellular defense under stress condition, a number of studies in recent years have shown the immense potential of hsp70 in pollution monitoring using even transgenic approach both in vivo and in vitro. This article reviews the recent developments in the widespread application of hsp70 in environmental risk assessment. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:249–254, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10086
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Deoxyspergualin (DSG) is a potent immunosuppressant whose mechanism of action remains unknown. To elucidate its mechanism of action, an intracellular DSG binding protein was identified. DSG has now been shown to bind specifically to Hsc70, the constitutive or cognate member of the heat shock protein 70 (Hsp70) protein family. The members of the Hsp70 family of heat shock proteins are important for many cellular processes, including immune responses, and this finding suggests that heat shock proteins may represent a class of immunosuppressant binding proteins, or immunophilins, distinct from the previously identified cis-trans proline isomerases. DSG may provide a tool for understanding the function of heat shock proteins in immunological processes.
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As an important kind of nonspecific cytoprotective proteins,heat shock proteins(HSPs) play a vital role in the stress tolerance and stress protection of immune cells,acting as molecular chaperones or anti-apoptosis effects in the maintenance of the immune cells survival and the stability of the internal environment.HSP70 and HSP27 of small heat shock proteins(sHPSs),an important member of HSPs,have been proved to have significant effect on mediating the cell proliferation,differentiation and apoptosis process.In this paper,the protective effect of HSP70/HSP27 on immune cells under the condition of heat stress was reviewed.
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