Membrane-bound heat shock protein mHsp70 is required for migration and invasion of brain tumors.

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) neurooncological 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 chaperone cluster (including representatives of other families such as Hsp70, Hsc70, Hsp105, Hsp90), which in turn, during interactome analysis, was associated with proteins involved in cell migration (e.g., Rac1, RhoC, myosin-9). The use of small-molecule inhibitors of HSP70 (PES, JG-98) led to a significant 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 JG-98, 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.