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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    • "It is involved in the folding and stabilization of active client proteins under stress conditions (changing in temperature, pH, hypoxia . . . ) and acts with various co-chaperones that regulate its activity. Hsp90 also plays a key role in the maturation of proteins implicated in some oncogenic pathways and is up-regulated in stress conditions (Jego et al., 2013). Heat shock protein genes are under the control of the transcription factor Heat Shock factor-1 (Hsf-1) which is activated in cancer cells to promote several pathways involved in metabolism (anabolism), survival, proliferation, protein folding and interacts with hsp70, hsp40 and hsp27 target genes (Scherz-Shouval et al., 2014; Hanahan and Weinberg, 2011). "
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    ABSTRACT: 6BrCaQ is a promising anti-cancer agent derived from novobiocin, which has been shown to inhibit Hsp90. 6BrCaQ was loaded into nanometer-scaled phospholipid vesicles (liposomes) suitable for drug delivery to solid tumors. The effective incorporation of the drug within the phospholipid bilayer was investigated by differential scanning calorimetry. Liposomal 6BrCaQ showed good activity on PC-3 cell lines in vitro in terms of apoptosis induction and cell growth arrest in G2/M. Liposomes containing 6BrCaQ were also shown to slow down migration of PC-3 cells in presence of chemokine ligand 2 and to synergize with doxorubicin. Several Hsp90 targeting molecules like geldanamycin induce accumulation of Hsp70, leading to cytoprotection and often correlated with poor prognosis. In this study, we did not report any Hsp70 induction after treatment with liposomal 6BrCaQ but a decrease in Hsp90 and CDK-4 protein expression, indicating an effect on the chaperon machinery. Liposomal encapsulation of 6BrCaQ revealed promising anti-cancer effects and a better understanding of its mechanism of action.
    Full-text · Article · Dec 2015 · International Journal of Pharmaceutics
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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.
    Full-text · Article · Sep 2015 · Oncogene
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    • "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.
    Full-text · Article · May 2015 · The Journal of Cell Biology
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