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Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma
Glioblastomas are characterized by amplification of EGFR. Approximately half of tumors with EGFR over-expression also express a constitutively active ligand independent EGFR variant III (EGFRvIII). While current treatments emphasize surgery followed by radiation and chemotherapy with Temozolomide (T...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482605/ https://www.ncbi.nlm.nih.gov/pubmed/28410193 http://dx.doi.org/10.18632/oncotarget.16767 |
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author | Velpula, Kiran K. Guda, Maheedhara R. Sahu, Kamlesh Tuszynski, Jack Asuthkar, Swapna Bach, Sarah E. Lathia, Justin D. Tsung, Andrew J. |
author_facet | Velpula, Kiran K. Guda, Maheedhara R. Sahu, Kamlesh Tuszynski, Jack Asuthkar, Swapna Bach, Sarah E. Lathia, Justin D. Tsung, Andrew J. |
author_sort | Velpula, Kiran K. |
collection | PubMed |
description | Glioblastomas are characterized by amplification of EGFR. Approximately half of tumors with EGFR over-expression also express a constitutively active ligand independent EGFR variant III (EGFRvIII). While current treatments emphasize surgery followed by radiation and chemotherapy with Temozolomide (TMZ), acquired chemoresistance is a universal feature of recurrent GBMs. To mimic the GBM resistant state, we generated an in vitro TMZ resistant model and demonstrated that dichloroacetate (DCA), a metabolic inhibitor of pyruvate dehydrogenase kinase 1 (PDK1), reverses the Warburg effect. Microarray analysis conducted on the TMZ resistant cells with their subsequent treatment with DCA revealed PDK1 as its sole target. DCA treatment also induced mitochondrial membrane potential change and apoptosis as evidenced by JC-1 staining and electron microscopic studies. Computational homology modeling and docking studies confirmed DCA binding to EGFR, EGFRvIII and PDK1 with high affinity. In addition, expression of EGFRvIII was comparable to PDK1 when compared to EGFR in GBM surgical specimens supporting our in silico prediction data. Collectively our current study provides the first in vitro proof of concept that DCA reverses the Warburg effect in the setting of EGFRvIII positivity and TMZ resistance leading to GBM cytotoxicity, implicating cellular tyrosine kinase signaling in cancer cell metabolism. |
format | Online Article Text |
id | pubmed-5482605 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-54826052017-06-27 Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma Velpula, Kiran K. Guda, Maheedhara R. Sahu, Kamlesh Tuszynski, Jack Asuthkar, Swapna Bach, Sarah E. Lathia, Justin D. Tsung, Andrew J. Oncotarget Research Paper Glioblastomas are characterized by amplification of EGFR. Approximately half of tumors with EGFR over-expression also express a constitutively active ligand independent EGFR variant III (EGFRvIII). While current treatments emphasize surgery followed by radiation and chemotherapy with Temozolomide (TMZ), acquired chemoresistance is a universal feature of recurrent GBMs. To mimic the GBM resistant state, we generated an in vitro TMZ resistant model and demonstrated that dichloroacetate (DCA), a metabolic inhibitor of pyruvate dehydrogenase kinase 1 (PDK1), reverses the Warburg effect. Microarray analysis conducted on the TMZ resistant cells with their subsequent treatment with DCA revealed PDK1 as its sole target. DCA treatment also induced mitochondrial membrane potential change and apoptosis as evidenced by JC-1 staining and electron microscopic studies. Computational homology modeling and docking studies confirmed DCA binding to EGFR, EGFRvIII and PDK1 with high affinity. In addition, expression of EGFRvIII was comparable to PDK1 when compared to EGFR in GBM surgical specimens supporting our in silico prediction data. Collectively our current study provides the first in vitro proof of concept that DCA reverses the Warburg effect in the setting of EGFRvIII positivity and TMZ resistance leading to GBM cytotoxicity, implicating cellular tyrosine kinase signaling in cancer cell metabolism. Impact Journals LLC 2017-03-31 /pmc/articles/PMC5482605/ /pubmed/28410193 http://dx.doi.org/10.18632/oncotarget.16767 Text en Copyright: © 2017 Velpula et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Velpula, Kiran K. Guda, Maheedhara R. Sahu, Kamlesh Tuszynski, Jack Asuthkar, Swapna Bach, Sarah E. Lathia, Justin D. Tsung, Andrew J. Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma |
title | Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma |
title_full | Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma |
title_fullStr | Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma |
title_full_unstemmed | Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma |
title_short | Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma |
title_sort | metabolic targeting of egfrviii/pdk1 axis in temozolomide resistant glioblastoma |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482605/ https://www.ncbi.nlm.nih.gov/pubmed/28410193 http://dx.doi.org/10.18632/oncotarget.16767 |
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