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The endoplasmic reticulum protein folding factory and its chaperones: New targets for drug discovery?

Institute of Cancer Research, London, UK.
British Journal of Pharmacology (Impact Factor: 4.99). 10/2010; 162(2):328-45. DOI: 10.1111/j.1476-5381.2010.01064.x
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ABSTRACT Cytosolic heat shock proteins have received significant attention as emerging therapeutic targets. Much of this excitement has been triggered by the discovery that HSP90 plays a central role in the maintenance and stability of multifarious oncogenic membrane receptors and their resultant tyrosine kinase activity. Numerous studies have dealt with the effects of small molecules on chaperone- and stress-related pathways of the endoplasmic reticulum (ER). However, unlike cytosolic chaperones, relatively little emphasis has been placed upon translational avenues towards targeting of the ER for inhibition of folding/secretion of disease-promoting proteins. Here, we summarise existing small molecule inhibitors and potential future targets of ER chaperone-mediated inhibition. Client proteins of translational relevance in disease treatment are outlined, alongside putative future disease treatment modalities based on ER-centric targeted therapies. Particular attention is paid to cancer and autoimmune disorders via the effects of the GRP94 inhibitor geldanamycin and its population of client proteins, overloading of the unfolded protein response, and inhibition of members of the IL-12 family of cytokines by celecoxib and non-coxib analogues.

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Available from: Koen Vandenbroeck, Jan 13, 2015
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    • "E-mail: mkumari@vet.ksu.edu cells or are integrated into cell membranes (Roth et al., 2003, 2010; Trombetta and Parodi, 2003). Studies involving the use of GI/GII inhibitors have shown a substantial reduction in cell proliferation/migration (Pili et al., 1995) and incorporation of incorrectly folded proteins into the cell membranes (Chapel et al., 2007), prompting their use as drugs to curtail cell proliferation and migration in diseases such as cancer, viral infection, and diabetes (Pili et al., 1995; Asano, 2003; Hwu et al., 2003; Chapel et al., 2007; van de Laar, 2008; McLaughlin and Vandenbroeck, 2011). Given the importance of the GII enzyme in cell physiology, little is known about its expression in various tissues, including brain tissues, even though its presence in the brain was first reported in 1979 (Scher and Waechter, 1979; Tulsiani et al., 1990). "
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    • "This discovery of a link between ER stress and disease onset indicates that unfolded proteins play a role in the etiology of many of the most prevalent diseases. It has been suggested that therapeutic drug targeting and other interventions aimed at disrupting the ER stress cycle in such diseases would provide a useful treatment strategy [25] [26] [27]. Here we review recent evidence for the involvement of ER stress in PD. "
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