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: 4.84). 10/2010; 162(2):328-45. DOI: 10.1111/j.1476-5381.2010.01064.x
Source: PubMed


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: 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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    ABSTRACT: α-Glucosidase II (GII), a resident of endoplasmic reticulum (ER) and an important enzyme in the folding of nascent glycoproteins, is heterodimeric, consisting of α (GIIα) and β (GIIβ) subunits. The catalytic GIIα subunit, with the help of mannose 6-phosphate receptor homology domain of GIIβ, sequentially hydrolyzes two α1-3-linked glucose residues in the second step of N-linked oligosaccharide-mediated protein folding. The soluble GIIα subunit is retained in the ER through its interaction with the HDEL-containing GIIβ subunit. N-glycosylation and correct protein folding are crucial for protein stability and trafficking and cell surface expression of several proteins in the brain. Alterations in N-glycosylation lead to abnormalities in neuronal migration and mental retardation, various neurodegenerative diseases, and invasion of malignant gliomas. Inhibitors of GII are used to inhibit cell proliferation and migration in a variety of different pathologies, such as viral infection, cancer, and diabetes. Despite the widespread use of GIIα inhibitory drugs and the role of GIIα in brain function, little is known about its expression in brain and other tissues. Here, we report generation of a highly specific chicken antibody to the GIIα subunit and its characterization by Western blotting and immunoprecipitation using cerebral cortical extracts. By using this antibody, we showed that the GIIα protein is highly expressed in testis, kidney, and lung, with the lowest amount in heart. GIIα polypeptide levels in whole brain were comparable to those in spleen. However, a higher expression of GIIα protein was detected in the cerebral cortex, reflecting its continuous requirement in correct folding of cell surface proteins. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 01/2015; 93(1). DOI:10.1002/jnr.23470 · 2.59 Impact Factor
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    • "Traditionally, the unfolded protein response directed by proteins that include CHOP, IRE1α, PERK as well as others is to promote cell survival [7]. There are clearly instances where this is true, however, there is evidence linking proteins associated with the UPR in promoting degradation of key proteins [10], [11]. "
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    ABSTRACT: The Mediterranean diet has long been attributed to preventing or delaying the onset of cardiovascular disease, diabetes and various solid organ cancers. In this particular study, a rosemary extract standardized to carnosic acid was evaluated for its potential in disrupting the endoplasmic reticulum machinery to decrease the viability of prostate cancer cells and promote degradation of the androgen receptor. Two human prostate cancer cell lines, 22Rv1 and LNCaP, and prostate epithelial cells procured from two different patients undergoing radical prostatectomy were treated with standardized rosemary extract and evaluated by flow cytometry, MTT, BrdU, Western blot and fluorescent microscopy. A significant modulation of endoplasmic reticulum stress proteins was observed in cancer cells while normal prostate epithelial cells did not undergo endoplasmic reticulum stress. This biphasic response suggests that standardized rosemary extract may preferentially target cancer cells as opposed to "normal" cells. Furthermore, we observed standardized rosemary extract to decrease androgen receptor expression that appears to be regulated by the expression of CHOP/GADD153. Using a xenograft tumor model we observed standardized rosemary extract when given orally to significantly suppress tumor growth by 46% compared to mice not receiving standardized rosemary extract. In the last several years regulatory governing bodies (e.g. European Union) have approved standardized rosemary extracts as food preservatives. These results are especially significant as it is becoming more likely that individuals will be receiving standardized rosemary extracts that are a part of a natural preservative system in various food preparations. Taken a step further, it is possible that the potential benefits that are often associated with a "Mediterranean Diet" in the future may begin to extend beyond the Mediterranean diet as more of the population is consuming standardized rosemary extracts.
    PLoS ONE 03/2014; 9(3):e89772. DOI:10.1371/journal.pone.0089772 · 3.23 Impact Factor
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    • "Previously, we have demonstrated that TFM-C inhibits secretion of the (hetero)dimeric IL-12 family cytokines IL-12, p402 and IL-23 through a Ca2+-dependent mechanism involving chaperone-mediated cytokine retention in the ER coupled to degradation via HERP protein, and that TFM-C dramatically upregulates HERP gene expression in various cell lines [5,6,9]. In organotypic cultures, virtually no effect was seen on mRNA production of HERP at 6 and 12 hours of LPS/TFM-C treatment in compared with LPS stimulation (Figure 1B). "
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    ABSTRACT: Celecoxib is a selective cyclooxygenase-2 (COX2) inhibitor. We have previously shown that celecoxib inhibits experimental autoimmune encephalomyelitis (EAE) in COX-2-deficient mice, suggestive for a mode of action involving COX2-independent pathways. In the present study, we tested the effect of a trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2 inhibitory activity in two models of neuroinflammation, i.e. cerebellar organotypic cultures challenged with LPS and the EAE mouse model for multiple sclerosis. TFM-C inhibited secretion of IL-1β, IL-12 and IL-17, enhanced that of TNF-α and RANTES, reduced neuronal axonal damage and protected from oxidative stress in the organotypic model. TFM-C blocked TNF-α release in microglial cells through a process involving intracellular retention, but induced TNF-α secretion in primary astrocyte cultures. Finally, we demonstrate that TFM-C and celecoxib ameliorated EAE with equal potency. This coincided with reduced secretion of IL-17 and IFN-γ by MOG-reactive T-cells and of IL-23 and inflammatory cytokines by bone marrow-derived dendritic cells. Our study reveals that non-coxib analogues of celecoxib may have translational value in the treatment of neuro-inflammatory conditions.
    PLoS ONE 12/2013; 8(12):e83119. DOI:10.1371/journal.pone.0083119 · 3.23 Impact Factor
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