Article

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

ABSTRACT

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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    • "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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    • "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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