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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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. |
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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.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms22041520</identifier><identifier>PMID: 33546324</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>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</subject><ispartof>International journal of molecular sciences, 2021-02, Vol.22 (4), p.1520</ispartof><rights>2021. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). 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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.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Brain cancer</subject><subject>Cell death</subject><subject>Cell growth</subject><subject>Cell Hypoxia</subject><subject>Cell Line</subject><subject>Cobalt</subject><subject>Cobalt chloride</subject><subject>Colchicine</subject><subject>Enzymes</subject><subject>Glioblastoma</subject><subject>Glioblastoma - metabolism</subject><subject>Glioblastoma - physiopathology</subject><subject>Glioblastoma cells</subject><subject>Glyceraldehyde-3-phosphate dehydrogenase</subject><subject>Glyceraldehyde-3-Phosphate Dehydrogenases - chemistry</subject><subject>Glyceraldehyde-3-Phosphate Dehydrogenases - metabolism</subject><subject>HEK293 Cells</subject><subject>HSP70 Heat-Shock Proteins - metabolism</subject><subject>Hsp70 protein</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Motility</subject><subject>Oxidation-Reduction</subject><subject>Protein Aggregates</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Rats</subject><subject>Tumorigenicity</subject><subject>Tumors</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkU1rFTEUhoMo9kN3riXgxkWv5nPSbIQy1XsLhQrVdchkzthcZiZjTkZbf71T-8Gtq3PgPLycl4eQN5x9kNKyj3E7oBBMcS3YM7LPlRArxirzfGffIweIW8aEFNq-JHtSalVJofZJexoxz1OJaaSpo-UKaJ2GqYdr2kD5DTDS9cnX0w31Y0s3OBlGL2HEWOIfQFpXdN3H1PQeSxo8raHvkZZENzdTuo6BXpYMiK_Ii873CK_v5yH5_uXzt3qzOr9Yn9Un56uguCgrwVvwDVc6aAu60Uwaq7XklQgBlDCMMy86ULrpQEjuvZadrILh1mrbBisPyae73GluBmgDjCX73k05Dj7fuOSje3oZ45X7kX45Y7nUx7cB7-8Dcvo5AxY3RAxLKT9CmtEJdWy4rqQ2C_ruP3Sb5jwu9f5RQivD1UId3VEhJ8QM3eMznLlbfW5X34K_3S3wCD_4kn8BybeVWA</recordid><startdate>20210203</startdate><enddate>20210203</enddate><creator>Mikeladze, Marina A</creator><creator>Dutysheva, Elizaveta A</creator><creator>Kartsev, Victor G</creator><creator>Margulis, Boris A</creator><creator>Guzhova, Irina V</creator><creator>Lazarev, Vladimir F</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7117-6789</orcidid><orcidid>https://orcid.org/0000-0002-8775-7713</orcidid></search><sort><creationdate>20210203</creationdate><title>Disruption of the Complex between GAPDH and Hsp70 Sensitizes C6 Glioblastoma Cells to Hypoxic Stress</title><author>Mikeladze, Marina A ; 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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.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33546324</pmid><doi>10.3390/ijms22041520</doi><orcidid>https://orcid.org/0000-0002-7117-6789</orcidid><orcidid>https://orcid.org/0000-0002-8775-7713</orcidid><oa>free_for_read</oa></addata></record> |
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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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