Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis
Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis
复制标题
DOI：
10.1038/nm.2457
复制
发表时间：
2011-10-01
期刊：
影响因子：
82.9
通讯作者：
Duval, Alex
中科院分区：
文献类型：
--
作者：
Dorard, Coralie;de Thonel, Aurelie;Duval, Alex
热休克蛋白（HSP）是癌细胞生存所必需的。我们鉴定了结肠直肠癌中的HSP 110突变体（HSP 110 Delta E9），该突变体显示微卫星不稳定性（MSI CRC），由异常剪接的mRNA产生，缺乏HSP 110底物结合结构域。该突变体在几乎所有MSI CRC细胞系和测试的原发性肿瘤中以可变水平表达。HSP 11 Delta DE 9损害了HSP 110的正常细胞定位及其与其他HSP的相互作用，从而以显性负性方式废除了HSP 110的分子伴侣活性和抗凋亡功能。HSP 110 Delta E9过表达导致细胞对抗癌药物如奥沙利铂和5-氟尿嘧啶敏感，这些药物是CRC患者辅助治疗的常规处方。MSI CRC患者的生存率和对化疗的反应与HSP 110 Delta E9的表达水平相关。因此，HSP 110可能构成CRC预后和治疗反应的主要决定因素。
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.