Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis

被引：126

作者：

Dorard, Coralie ^{[1
,2
]}

de Thonel, Aurelie ^{[3
,4
]}

Collura, Ada ^{[1
,2
]}

Marisa, Laetitia ^{[5
]}

Svrcek, Magali ^{[1
,2
,6
]}

Lagrange, Anais ^{[1
,2
]}

Jego, Gaetan ^{[3
,4
]}

Wanherdrick, Kristell ^{[1
,2
]}

Joly, Anne Laure ^{[3
,4
]}

Buhard, Olivier ^{[1
,2
]}

Gobbo, Jessica ^{[3
,4
]}

Penard-Lacronique, Virginie ^{[7
]}

Zouali, Habib ^{[8
]}

Tubacher, Emmanuel ^{[8
]}

Kirzin, Sylvain ^{[9
]}

Selves, Janick ^{[9
]}

Milano, Gerard ^{[10
]}

Etienne-Grimaldi, Marie-Christine ^{[10
]}

Bengrine-Lefevre, Leila ^{[11
]}

Louvet, Christophe ^{[11
]}

Tournigand, Christophe ^{[11
]}

Lefevre, Jeremie H. ^{[2
,12
]}

Parc, Yann ^{[2
,12
]}

Tiret, Emmanuel ^{[2
,12
]}

Flejou, Jean-Francois ^{[1
,2
,13
]}

Gaub, Marie-Pierre ^{[14
]}

Garrido, Carmen ^{[3
,4
,15
]}

Duval, Alex ^{[1
,2
]}

机构：

[1] INSERM, Ctr Rech St Antoine, Equipe Instabilite Microsatellites & Canc, Paris, France

[2] Univ Paris 06, Paris, France

[3] INSERM, Dijon, France

[4] Univ Burgundy, Dijon, France

[5] Programme Cartes Identite Tumeurs, Paris, France

[6] Hop St Antoine, AP HP, Serv Anat & Cytol Pathol, F-75571 Paris, France

[7] Inst Gustave Roussy, INSERM, F-94805 Villejuif, France

[8] Inst Genet Mol, Ctr Etud Polymorphisme Humain, Fdn Jean Dausset, Paris, France

[9] Ctr Physiopathol Toulouse Purpan, INSERM, Toulouse, France

[10] Ctr Antoine Lacassagne, Lab Oncopharmacol, F-06054 Nice, France

[11] Hop St Antoine, AP HP, Med Oncol Serv, F-75571 Paris, France

[12] Hop St Antoine, AP HP, Serv Chirurg Gen & Digest, F-75571 Paris, France

[13] Hop St Antoine, AP HP, Tumorotheque Canc Est, F-75571 Paris, France

[14] INSERM, Strasbourg, France

[15] Ctr Hosp Univ Dijon, Dijon, France

来源：

NATURE MEDICINE | 2011年 / 17卷 / 10期

关键词：

MICROSATELLITE INSTABILITY; MONONUCLEOTIDE REPEATS; INDUCED APOPTOSIS; MISMATCH REPAIR; TARGET GENES; MUTATIONS; HEAT-SHOCK-PROTEIN-105; MECHANISM; SEQUENCES; PATHWAY;

D O I：

10.1038/nm.2457

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Heat shock proteins (HSPs) are necessary for cancer cell survival. We identified a mutant of HSP110 (HSP110 Delta E9) 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. HSP11 Delta DE9 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. HSP110 Delta E9 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 HSP110 Delta E9. HSP110 may thus constitute a major determinant for both prognosis and treatment response in CRC.

引用

页码：1283 / U316

页数：8

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