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Coralie Dorard,
Aurélie de Thonel,
Ada Collura,
Laetitia Marisa,
Magali Svrcek,
Anaïs Lagrange,
Gaetan Jego,
Kristell Wanherdrick,
Anne Laure Joly,
Olivier Buhard, [......],
Leila Bengrine-Lefèvre,
Christophe Louvet,
Christophe Tournigand,
Jérémie H Lefèvre,
Yann Parc,
Emmanuel Tiret,
Jean-François Fléjou,
Marie-Pierre Gaub,
Carmen Garrido,
Alex Duval
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ABSTRACT: Heat shock proteins (HSPs) are necessary for cancer cell survival. We identified a mutant of HSP110 (HSP110ΔE9) in colorectal cancer showing microsatellite instability (MSI CRC), generated from an aberrantly spliced mRNA and lacking the HSP110 substrate-binding domain. This mutant was expressed at variable levels in almost all MSI CRC cell lines and primary tumors tested. HSP110ΔE9 impaired both the normal cellular localization of HSP110 and its interaction with other HSPs, thus abrogating the chaperone activity and antiapoptotic function of HSP110 in a dominant-negative manner. HSP110ΔE9 overexpression caused the sensitization of cells to anticancer agents such as oxaliplatin and 5-fluorouracil, which are routinely prescribed in the adjuvant treatment of people with CRC. The survival and response to chemotherapy of subjects with MSI CRCs was associated with the tumor expression level of HSP110ΔE9. HSP110 may thus constitute a major determinant for both prognosis and treatment response in CRC.
Nature medicine 09/2011; 17(10):1283-9. · 27.14 Impact Factor
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ABSTRACT: A major endeavour in cancer chemotherapy is to develop agents that specifically target a biomolecule of interest. There are two main classes of targeting agents: small molecules and biologics. Among biologics (e.g.: antibodies), DNA, RNA but also peptide aptamers are relatively recent agents. Peptide aptamers are seldom described but represent attractive agents that can inhibit a growing panel of oncotargets including Heat Shock Proteins. Potential pitfalls and coming challenges towards successful clinical trials are presented such as optimizing the delivery of peptide aptamers thanks to Nanotechnology.
Oncotarget 06/2011; 2(7):557-61. · 4.78 Impact Factor
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ABSTRACT: Stress-inducible heat-shock proteins (HSPs, like HSP70 and HSP27) are molecular chaperones that -protect cells from stress damage by keeping cellular proteins in a folding competent state and preventing them from irreversible aggregation. HSP27 and HSP70 chaperone activities are useful indicators to test chemical products and physical stress impact on protein denaturation, to select HSP inhibitors, or to -determine the implication of the chaperone function in other HSP activities, such as apoptosis. We have developed two simple and fast chaperone activity tests for HSP27 and HSP70 that we initially set up to test the effect of potential HSP inhibitors obtained after screening of chemical and small molecule libraries. These chaperone quantification tests are based on the capacity of HSP to counteract chemical or thermal protein aggregation.
Methods in molecular biology (Clifton, N.J.) 01/2011; 787:137-43.
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Anne-Laure Rérole, Jessica Gobbo,
Aurelie De Thonel,
Elise Schmitt,
Jean Paul Pais de Barros,
Arlette Hammann,
David Lanneau,
Eric Fourmaux,
Oleg Deminov,
Olivier Micheau,
Laurent Lagrost,
Pierre Colas,
Guido Kroemer,
Carmen Garrido
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ABSTRACT: The inhibition of heat shock protein 70 (HSP70) is an emerging strategy in cancer therapy. Unfortunately, no specific inhibitors are clinically available. By yeast two-hybrid screening, we have identified multiple peptide aptamers that bind HSP70. When expressed in human tumor cells, two among these peptide aptamers-A8 and A17-which bind to the peptide-binding and the ATP-binding domains of HSP70, respectively, specifically inhibited the chaperone activity, thereby increasing the cells' sensitivity to apoptosis induced by anticancer drugs. The 13-amino acid peptide from the variable region of A17 (called P17) retained the ability to specifically inhibit HSP70 and induced the regression of subcutaneous tumors in vivo after local or systemic injection. This antitumor effect was associated with an important recruitment of macrophages and T lymphocytes into the tumor bed. Altogether, these data indicate that peptide aptamers or peptides that target HSP70 may be considered as novel lead compounds for cancer therapy.
Cancer Research 01/2011; 71(2):484-95. · 7.86 Impact Factor
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ABSTRACT: First discovered in 1962, heat shock proteins (HSPs) are highly studied with about 35,500 publications on the subject to date. HSPs are highly conserved, function as molecular chaperones for a large panel of "client" proteins and have strong cytoprotective properties. Induced by many different stress signals, they promote cell survival in adverse conditions. Therefore, their roles have been investigated in several conditions and pathologies where HSPs accumulate, such as in cancer. Among the diverse mammalian HSPs, some members share several features that may qualify them as cancer biomarkers. This review focuses mainly on three inducible HSPs: HSP27, HPS70, and HSP90. Our survey of recent literature highlights some recurring weaknesses in studies of the HSPs, but also identifies findings that indicate that some HSPs have potential as cancer biomarkers for successful clinical applications.
Frontiers in oncology. 01/2011; 1:37.
