分子伴侣,尤其是70kDa的热休克蛋白,除了它们在癌细胞中的细胞内定位,可以暴露在质膜表面。我们报告说,恶性脑肿瘤的膜相关分子伴侣mHsp70是癌细胞高迁移和侵袭活性所必需的。成人(n=23)和儿科(n=9)神经肿瘤患者的肿瘤样品的活细胞倒置共聚焦显微镜显示膜上有明显的蛋白质表达,尤其是在近焦区域.从肿瘤细胞中分离的脂筏的质谱分析证实了伴侣簇(包括其他家族的代表,例如Hsp70,Hsc70,Hsp105,Hsp90)中蛋白质的存在,反过来,在相互作用组分析期间,与参与细胞迁移的蛋白质相关(例如,Rac1,RhoC,肌球蛋白-9)。使用HSP70的小分子抑制剂(PES,JG-98)导致从患者肿瘤样本中分离出的细胞的侵袭潜能显着降低,这表明了伴侣在入侵中的作用。此外,在原位脑肿瘤动物模型中使用HSP70抑制剂显著延迟肿瘤进展,伴随着总生存期的增加。数据表明,伴侣抑制剂,特别是JG-98,破坏了mHsp70的功能,从而提供了更好地了解这种蛋白质的多种功能的机会,并为新型癌症疗法的开发提供了帮助。
Molecular chaperones, especially 70 kDa heat shock protein, in addition to their intracellular localization in cancer cells, can be exposed on the surface of the plasma membrane. We report that the membrane-associated chaperone mHsp70 of malignant brain tumors is required for high migratory and invasive activity of cancer cells. Live-cell inverted confocal microscopy of tumor samples from adult (n = 23) and pediatric (n = 9) neurooncologic patients showed pronounced protein expression on the membrane, especially in the perifocal zone. Mass spectrometry analysis of lipid rafts isolated from tumor cells confirmed the presence of the protein in the chaperone cluster (including representatives of other families, such as Hsp70, Hsc70, Hsp105, and Hsp90), which in turn, during interactome analysis, was associated with proteins involved in cell migration (e.g., Rac1, RhoC, and myosin-9). The use of small-molecule inhibitors of HSP70 (PES and JG98) led to a substantial decrease in the invasive potential of cells isolated from a tumor sample of patients, which indicates the role of the chaperone in invasion. Moreover, the use of HSP70 inhibitors in animal models of orthotopic brain tumors significantly delayed tumor progression, which was accompanied by an increase in overall survival. Data demonstrate that chaperone inhibitors, particularly JG98, disrupt the function of mHsp70, thereby providing an opportunity to better understand the diverse functions of this protein and offer aid in the development of novel cancer therapies.
UNASSIGNED: Membrane-bound mHsp70 is required for brain tumor cell migration and invasion and therefore could be employed as a target for anticancer therapies.