TY - JOUR
T1 - Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis
AU - Dorard, Coralie
AU - De Thonel, Aurélie
AU - Collura, Ada
AU - Marisa, Laetitia
AU - Svrcek, Magali
AU - Lagrange, Anaïs
AU - Jego, Gaetan
AU - Wanherdrick, Kristell
AU - Joly, Anne Laure
AU - Buhard, Olivier
AU - Gobbo, Jessica
AU - Penard-Lacronique, Virginie
AU - Zouali, Habib
AU - Tubacher, Emmanuel
AU - Kirzin, Sylvain
AU - Selves, Janick
AU - Milano, Gérard
AU - Etienne-Grimaldi, Marie Christine
AU - Bengrine-Lefevre, Leila
AU - Louvet, Christophe
AU - Tournigand, Christophe
AU - Lefvre, Jérémie H.
AU - Parc, Yann
AU - Tiret, Emmanuel
AU - Fléjou, Jean François
AU - Gaub, Marie Pierre
AU - Garrido, Carmen
AU - Duval, Alex
N1 - Funding Information:
This work was supported by the Carte d’Identité des Tumeurs (CIT) program (http://cit.liguecancer.net/) from the Ligue Nationale Contre le Cancer and by grants from the Fondation de France (Ref. RAF08005DDA to A.D.), the Institut National du Cancer (INCa) (to A.D. and C.G.), the Conseil Regional de Bourgogne (to C.G.) and the European Commission Seventh Framework Programme (SPEDOC 248835 to C.G.). C.G.’s group is known as ‘La Ligue Contre le Cancer’. A.C. is a recipient of an INCa fellowship. We thank B. Iacopetta for critical reading of the manuscript. We thank E. Roux, A. Hamman, E. Fourmaux and E. Bergman for their technical assistance.
PY - 2011/10/1
Y1 - 2011/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80053987011&partnerID=8YFLogxK
U2 - 10.1038/nm.2457
DO - 10.1038/nm.2457
M3 - Article
C2 - 21946539
AN - SCOPUS:80053987011
SN - 1078-8956
VL - 17
SP - 1283
EP - 1289
JO - Nature Medicine
JF - Nature Medicine
IS - 10
ER -