Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response

SIMPLE SUMMARY: Ionizing radiation is a major pillar in the therapy of solid tumors. However, normal tissue toxicities and radioresistance of tumor cells can limit the therapeutic success of radiotherapy. In this study, we investigated the coregulation of the cancer metabolism and the heat shock response with respect to radioresistance. Our results indicate that an inhibition of lactate dehydrogenase, either pharmacologically or by gene knockout of LDHA and LDHB, significantly increases the radiosensitivity in tumor cells by global impairing of the stress response. Therefore, inhibition of the lactate metabolism might provide a promising strategy in the future to improve the clinical outcome of patients with highly aggressive, therapy-resistant tumors. ABSTRACT: The heightened energetic demand increases lactate dehydrogenase (LDH) activity, the corresponding oncometabolite lactate, expression of heat shock proteins (HSPs) and thereby promotes therapy resistance in many malignant tumor cell types. Therefore, we assessed the coregulation of LDH and the heat shock response with respect to radiation resistance in different tumor cells (B16F10 murine melanoma and LS174T human colorectal adenocarcinoma). The inhibition of LDH activity by oxamate or GNE-140, glucose deprivation and LDHA/B double knockout (LDH(−)(/)(−)) in B16F10 and LS174T cells significantly diminish tumor growth; ROS production and the cytosolic expression of different HSPs, including Hsp90, Hsp70 and Hsp27 concomitant with a reduction of heat shock factor 1 (HSF1)/pHSF1. An altered lipid metabolism mediated by a LDHA/B double knockout results in a decreased presence of the Hsp70-anchoring glycosphingolipid Gb3 on the cell surface of tumor cells, which, in turn, reduces the membrane Hsp70 density and increases the extracellular Hsp70 levels. Vice versa, elevated extracellular lactate/pyruvate concentrations increase the membrane Hsp70 expression in wildtype tumor cells. Functionally, an inhibition of LDH causes a generalized reduction of cytosolic and membrane-bound HSPs in tumor cells and significantly increases the radiosensitivity, which is associated with a G2/M arrest. We demonstrate that targeting of the lactate/pyruvate metabolism breaks the radioresistance by impairing the stress response.