Dataset Information

Impaired stability of tumor cells after targeting of lactate/pyruvate metabolism investigated by shotgun proteomics

ABSTRACT: Overexpression of heat shock proteins (HSPs), especially the major stress-inducible 72 kDa heat shock protein 70 (Hsp70), in malignant tumor cells is associated with therapeutic resistance. The heightened metabolic demand in tumor cells (Warburg effect) increases lactate dehydrogenase (LDH) activity and the corresponding increase in lactate concentrations promotes malignancy. Herein, we assessed the co-regulation of LDH and the heat shock response and its link to radiation resistance in B16F10 murine melanoma cells and LS174T human colorectal adenocarcinoma cells. Inhibition of LDHA/B by oxamate or GNE-140, significantly diminishes the expression of Hsp90, Hsp70 and Hsp27 in the cytosol. Diminished expression was also observed in LDHA/B double knockout (LDH-/-) cells. An increased production of reactive oxygen species (ROS) induced by a faster growth rate in wild type (WT) vs LDH-/- cells contributes to increased cytosolic HSP levels in WT cells. LDH-/- cells exhibit a lower density of membrane Hsp70 expression than WT cells and a decreased presence of the tumor-specific, Hsp70 anchoring glycosphingolipid Gb3 on the cell surface which could be attributed to an altered lipid metabolism mediated by the LDH knockout. Functionally, a double knockout of LDHA/B results in a generalized reduction in expression of HSPs in tumor cells and significantly increases radiosensitivity which is associated with a G2/M arrest. In summary, we demonstrate that pharmacological targeting of the lactate/pyruvate metabolism breaks radioresistance by impairing the stress response.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Christine von Toerne

LAB HEAD: Gabriele Multhoff

PROVIDER: PXD026078 | Pride | 2022-02-17

REPOSITORIES: Pride

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			Action	DRS
	AZO13579-_1_.msf	Msf
	AZO13579X002__Wild_1_92-221672.raw	Raw
	AZO13579X003__Wild_2_92-221671.raw	Raw
	AZO13579X004__Wild_3_92-221674.raw	Raw
	AZO13579X005__Wild_4_92-221673.raw	Raw

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Publications

Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response.

Schwab Melissa M Thunborg Katharina K Azimzadeh Omid O von Toerne Christine C Werner Caroline C Shevtsov Maxim M Di Genio Tommaso T Zdralevic Masa M Pouyssegur Jacques J Renner Kathrin K Kreutz Marina M Multhoff Gabriele G

Cancers 20210727 15

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, g ...[more]

PMID: 34359663

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