title: Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine, Equipe 'Instabilité des Microsatellites et Cancers', Paris, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Dorard
authors.forename: Aurélie
authors.initials: A
authors.lastname: de Thonel
authors.forename: Ada
authors.initials: A
authors.lastname: Collura
authors.forename: Laetitia
authors.initials: L
authors.lastname: Marisa
authors.forename: Magali
authors.initials: M
authors.lastname: Svrcek
authors.forename: Anaïs
authors.initials: A
authors.lastname: Lagrange
authors.forename: Gaetan
authors.initials: G
authors.lastname: Jego
authors.forename: Kristell
authors.initials: K
authors.lastname: Wanherdrick
authors.forename: Anne Laure
authors.initials: AL
authors.lastname: Joly
authors.forename: Olivier
authors.initials: O
authors.lastname: Buhard
authors.forename: Jessica
authors.initials: J
authors.lastname: Gobbo
authors.forename: Virginie
authors.initials: V
authors.lastname: Penard-Lacronique
authors.forename: Habib
authors.initials: H
authors.lastname: Zouali
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tubacher
authors.forename: Sylvain
authors.initials: S
authors.lastname: Kirzin
authors.forename: Janick
authors.initials: J
authors.lastname: Selves
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne-Grimaldi
authors.forename: Leila
authors.initials: L
authors.lastname: Bengrine-Lefèvre
authors.forename: Christophe
authors.initials: C
authors.lastname: Louvet
authors.forename: Christophe
authors.initials: C
authors.lastname: Tournigand
authors.forename: Jérémie H
authors.initials: JH
authors.lastname: Lefèvre
authors.forename: Yann
authors.initials: Y
authors.lastname: Parc
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tiret
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Fléjou
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Gaub
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.forename: Alex
authors.initials: A
authors.lastname: Duval
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005472:Fluorouracil; D050957:HSP110 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010957:Plasmids / Q000235:genetics; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D012044:Regression Analysis; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D050957:HSP110 Heat-Shock Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005472:Fluorouracil