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Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis |
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| Authors: | Dorard Coralie de Thonel Aurélie Collura Ada Marisa Laetitia Svrcek Magali Lagrange Anaïs Jego Gaetan Wanherdrick Kristell Joly Anne Laure Buhard Olivier Gobbo Jessica Penard-Lacronique Virginie Zouali Habib Tubacher Emmanuel Kirzin Sylvain Selves Janick Milano Gérard Etienne-Grimaldi Marie-Christine Bengrine-Lefèvre Leila Louvet Christophe Tournigand Christophe Lefèvre Jérémie H Parc Yann Tiret Emmanuel Fléjou Jean-François Gaub Marie-Pierre Garrido Carmen Duval Alex |
| Institution: | Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine, Equipe 'Instabilité des Microsatellites et Cancers', Paris, France. |
| 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. |
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