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Schwab, M.* ; Thunborg, K.* ; Azimzadeh, O. ; von Toerne, C. ; Werner, C.* ; Shevtsov, M.* ; Di Genio, T.* ; Zdralevic, M.* ; Pouysségur, J.* ; Renner, K.* ; Kreutz, M.* ; Multhoff, G.*

Targeting cancer metabolism breaks radioresistance by impairing the stress response.

Cancers 13:3762 (2021)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Lactate/pyruvate Metabolism ; Ldha/b Double Knockout ; Membrane Heat Shock Protein 70 (hsp70) ; Radiosensitivity ; Stress Response; Heat-shock Proteins; Lactate-dehydrogenase; Heat-shock-protein-70 Hsp70; Inhibition; Chaperones; Proteome; Survival; Factor-1; Surface; Cells
ISSN (print) / ISBN 2072-6694
Zeitschrift Cancers
Quellenangaben Band: 13, Heft: 15, Seiten: , Artikelnummer: 3762 Supplement: ,
Verlag MDPI
Verlagsort St Alban-anlage 66, Ch-4052 Basel, Switzerland
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Radiation Medicine (IRM)
CF Metabolomics & Proteomics (CF-MPC)
Förderungen Bundesministerium für Wirtschaft und Energie
Deutsche Forschungsgemeinschaft