Targeting heat shock proteins in cancer

University of Burgundy, Esplanade Erasme, 21078 Dijon, France.
Cancer letters (Impact Factor: 5.62). 11/2010; 332(2). DOI: 10.1016/j.canlet.2010.10.014
Source: PubMed


Heat shock proteins (HSPs) HSP27, HSP70 and HSP90 are powerful chaperones. Their expression is induced in response to a wide variety of physiological and environmental insults including anti-cancer chemotherapy, thus allowing the cell to survive to lethal conditions. Different functions of HSPs have been described to account for their cytoprotective function, including their role as molecular chaperones as they play a central role in the correct folding of misfolded proteins, but also their anti-apoptotic properties. HSPs are often overexpressed in cancer cells and this constitutive expression is necessary for cancer cells' survival. HSPs may have oncogene-like functions and likewise mediate "non-oncogene addiction" of stressed tumor cells that must adapt to a hostile microenvironment, thereby becoming dependent for their survival on HSPs. HSP-targeting drugs have therefore emerged as potential anti-cancer agents. This review describes the different molecules and approaches being used or proposed in cancer therapy based on the in inhibition of HSP90, HSP70 and HSP27.

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Available from: Renaud Seigneuric, Jun 27, 2014
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    • "Currently, there are several inhibitors for HSP90 and HSP27 undergoing clinical trials (reviewed in Jego et al. [1]). The HSP90 inhibitors, most of them derived form the antibiotic geldanamycin, demonstrated potential efficiency in treatment of blood-related malignancies and many types of cancer including breast and lung cancer [1]. One of the side effects of HSP90 inhibition is the compensatory induction of HSP70 expression – a potent negative regulator of cell death. "
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    ABSTRACT: Graft versus host disease (GvHD), which is the primary complication of allogeneic bone marrow transplantation, can alter the intestinal barrier targeted by activated donor T-cells. Chemical inhibition of the stress protein HSP90 was demonstrated in vitro to inhibit T-cell activation and to modulate endoplasmic reticulum (ER) stress to which intestinal cells are highly susceptible. Since the HSP90 inhibitor 17-allylamino-demethoxygeldanamycin (17AAG) is developed in clinics, we explored here its ability to control intestinal acute GvHD in vivo in two mouse GvHD models (C57BL/6BALB/c and FVB/NLgr5-eGFP), ex vivo in intestine organoids and in vitro in intestinal epithelial cultures. We show that 17AAG decreases GvHD-associated mortality without impairing graft versus leukemia effect. While 17AAG effect in T-cell activation is just moderate at the dose used in vivo, we observe a striking intestinal integrity protection. At the intestine level, the drug promotes the splicing of the transcription factor X-box binding protein 1 (XBP1), which is a key component of the ER stress. This effect is associated with a decrease in intestinal damage and an increase in Lgr5(+) stem cells, Paneth cells and defensins production. The importance of XBP1 splicing control is further confirmed in cultured cells and organoids of primary intestinal epithelium where XBP1 is either shRNA depleted or inhibited with toyocamycin. In conclusion, 17AAG has a protective effect on the epithelial intestinal barrier in mouse models of acute GvHD. This compound deserves to be tested in the therapeutic control of acute GvHD.Oncogene advance online publication, 14 September 2015; doi:10.1038/onc.2015.242.
    Oncogene 09/2015; DOI:10.1038/onc.2015.242 · 8.46 Impact Factor
    • "These functions are essential in many biological contexts, including assembly of macromolecular complexes, protein trafficking, and regulation of enzyme activity (Bukau et al., 2006). HSPs are particularly important in cells subject to proteotoxic stress and are attracting considerable interest as potential targets for cancer therapy (Powers and Workman, 2007; Jego et al., 2013). The Hsp70 proteins represent a major family of HSPs that are frequently overexpressed in human cancers (Rohde et al., 2005; Daugaard et al., 2007; Kampinga and Craig, 2010). "
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    ABSTRACT: Hsp70 proteins represent a family of chaperones that regulate cellular homeostasis and are required for cancer cell survival. However, their function and regulation in mitosis remain unknown. In this paper, we show that the major inducible cytoplasmic Hsp70 isoform, Hsp72, is required for assembly of a robust bipolar spindle capable of efficient chromosome congression. Mechanistically, Hsp72 associates with the K-fiber-stabilizing proteins, ch-TOG and TACC3, and promotes their interaction with each other and recruitment to spindle microtubules (MTs). Targeting of Hsp72 to the mitotic spindle is dependent on phosphorylation at Thr-66 within its nucleotide-binding domain by the Nek6 kinase. Phosphorylated Hsp72 concentrates on spindle poles and sites of MT-kinetochore attachment. A phosphomimetic Hsp72 mutant rescued defects in K-fiber assembly, ch-TOG/TACC3 recruitment and mitotic progression that also resulted from Nek6 depletion. We therefore propose that Nek6 facilitates association of Hsp72 with the mitotic spindle, where it promotes stable K-fiber assembly through recruitment of the ch-TOG-TACC3 complex. © 2015 O’Regan et al.
    The Journal of Cell Biology 05/2015; 209(3). DOI:10.1083/jcb.201409151 · 9.83 Impact Factor
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    • "Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution License 4.0International License synthesized in eukaryotes belonging to six structurally distinct classes: Hsp100,Hsp90, Hsp70, Hsp60 (or chaperonins), ∼17-30 kDa small Hsps and ~8-5 kDa ubiquitin (Safdar et al., 2012). Hsp70 family chaperones are considered to be the most highly conserved heat shock proteins (Jego et al., 2013). In plants, many Hsp70 proteins have been identified in different species (Daugaard et al., 2007). "
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    ABSTRACT: TaHSC70 gene of Triticum sp. is an associate of the heat shock protein family and plays a significant role in stress-related and defense responses educed by contagion with stripe rust fungus through a Jasmonic acid dependent signal transduction pathway. Hence, understanding molecular structure and function of the protein coded by this gene is of paramount importance for plant biologists working on stripe rust. The present study was aimed at sequence and in silico structural analysis of Hsp70 protein coded by this gene, through comparative modeling approach. Validation of the overall folds and structure, errors over localized regions and stereo chemical parameters was carried out using PDBSum server. Structure was a monomer with seven sheets, 1 β-α-βunit, 12 hairpins, 13 β-bulges, 29 strands, 21 helices, 16 helix-helix interacs, 44 β-turns and 1 ϒ-turn. Two major domains were detected belonging to Hsp70 family while neural network analysis revealed protein to be highly phosphorylated at serine and threonine residues.
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