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As overexpression and membrane localization of stress proteins together with high lactate levels promote radioresistance in tumor cells, we studied the effect of the Hsp90 inhibitor NVP-AUY922 on the cytosolic and membrane expression of heat shock proteins (HSPs) and radiosensitivity in murine melanoma (B16F10) and human colorectal (LS174T) wildtype (WT) and  lactate dehydrogenases A/B  double knockout (LDH −/− ) tumor cells. Double knockout for  LDHA/B  has been found to reduce cytosolic as well as membrane HSP levels, whereas treatment with NVP-AUY922 stimulates the synthesis of Hsp27 and Hsp70, but does not affect membrane Hsp70 expression. Despite NVP-AUY922-inducing elevated levels of cytosolic HSP, radiosensitivity was significantly increased in WT cells and even more pronounced in LDH −/−  cells. An impaired lipid metabolism in LDH −/−  cells reduces the Hsp70 membrane-anchoring sphingolipid globotriaosylceramide (Gb3) and thereby results in a decreased Hsp70 cell surface density on tumor cells. Our results demonstrate that the membrane Hsp70 density, but not cytosolic HSP levels determines the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in LDH −/−  cells.

A Low Membrane Hsp70 Expression in Tumor Cells With Impaired Lactate Metabolism Mediates Radiosensitization by NVP-AUY922