Disruption of the Complex between GAPDH and Hsp70 Sensitizes C6 Glioblastoma Cells to Hypoxic Stress

Hypoxia, which commonly accompanies tumor growth, depending on its strength may cause the enhancement of tumorigenicity of cancer cells or their death. One of the proteins targeted by hypoxia is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and we demonstrated here that hypoxia mimicked by treat...

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Veröffentlicht in:International journal of molecular sciences 2021-02, Vol.22 (4), p.1520
Hauptverfasser: Mikeladze, Marina A, Dutysheva, Elizaveta A, Kartsev, Victor G, Margulis, Boris A, Guzhova, Irina V, Lazarev, Vladimir F
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container_issue 4
container_start_page 1520
container_title International journal of molecular sciences
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creator Mikeladze, Marina A
Dutysheva, Elizaveta A
Kartsev, Victor G
Margulis, Boris A
Guzhova, Irina V
Lazarev, Vladimir F
description Hypoxia, which commonly accompanies tumor growth, depending on its strength may cause the enhancement of tumorigenicity of cancer cells or their death. One of the proteins targeted by hypoxia is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and we demonstrated here that hypoxia mimicked by treating C6 rat glioblastoma cells with cobalt chloride caused an up-regulation of the enzyme expression, while further elevation of hypoxic stress caused the enzyme aggregation concomitantly with cell death. Reduction or elevation of GAPDH performed with the aid of specific shRNAs resulted in the augmentation of the tumorigenicity of C6 cells or their sensitization to hypoxic stress. Another hypoxia-regulated protein, Hsp70 chaperone, was shown to prevent the aggregation of oxidized GAPDH and to reduce hypoxia-mediated cell death. In order to release the enzyme molecules from the chaperone, we employed its inhibitor, derivative of colchicine. The compound was found to substantially increase aggregation of GAPDH and to sensitize C6 cells to hypoxia both in vitro and in animals bearing tumors with distinct levels of the enzyme expression. In conclusion, blocking the chaperonic activity of Hsp70 and its interaction with GAPDH may become a promising strategy to overcome tumor resistance to multiple environmental stresses and enhance existing therapeutic tools.
doi_str_mv 10.3390/ijms22041520
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subjects Animals
Apoptosis
Brain cancer
Cell death
Cell growth
Cell Hypoxia
Cell Line
Cobalt
Cobalt chloride
Colchicine
Enzymes
Glioblastoma
Glioblastoma - metabolism
Glioblastoma - physiopathology
Glioblastoma cells
Glyceraldehyde-3-phosphate dehydrogenase
Glyceraldehyde-3-Phosphate Dehydrogenases - chemistry
Glyceraldehyde-3-Phosphate Dehydrogenases - metabolism
HEK293 Cells
HSP70 Heat-Shock Proteins - metabolism
Hsp70 protein
Humans
Hypoxia
Motility
Oxidation-Reduction
Protein Aggregates
Protein Binding
Proteins
Rats
Tumorigenicity
Tumors
title Disruption of the Complex between GAPDH and Hsp70 Sensitizes C6 Glioblastoma Cells to Hypoxic Stress
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