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GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets

Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor, portending a median 13-month survival even following gross total resection with adjuvant chemotherapy and radiotherapy. This prognosis necessitates improved therapies for the disease. A target of interest for novel chemothe...

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Autores principales: Guda, Maheedhara R., Labak, Collin M., Omar, Sara Ibrahim, Asuthkar, Swapna, Airala, Subra, Tuszynski, Jack, Tsung, Andrew J., Velpula, Kiran K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771132/
https://www.ncbi.nlm.nih.gov/pubmed/31491891
http://dx.doi.org/10.3390/cancers11091308
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author Guda, Maheedhara R.
Labak, Collin M.
Omar, Sara Ibrahim
Asuthkar, Swapna
Airala, Subra
Tuszynski, Jack
Tsung, Andrew J.
Velpula, Kiran K.
author_facet Guda, Maheedhara R.
Labak, Collin M.
Omar, Sara Ibrahim
Asuthkar, Swapna
Airala, Subra
Tuszynski, Jack
Tsung, Andrew J.
Velpula, Kiran K.
author_sort Guda, Maheedhara R.
collection PubMed
description Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor, portending a median 13-month survival even following gross total resection with adjuvant chemotherapy and radiotherapy. This prognosis necessitates improved therapies for the disease. A target of interest for novel chemotherapies is the Warburg Effect, which describes the tumor’s shift away from oxidative phosphorylation towards glycolysis. Here, we elucidate GLUT1 (Glucose transporter 1) and one of its associated binding partners, TUBB4 (Tubulin 4), as potentially druggable targets in GBM. Using data mining approach, we demonstrate that GLUT1 is overexpressed as a function of tumor grade in astrocytoma’s and that its overexpression is associated with poorer prognosis. Using both mass spectrometry performed on hGBM (human glioblastoma patient specimen) and in silico modeling, we show that GLUT1 interacts with TUBB4, and more accurately demonstrates GLUT1’s binding with fasentin. Proximity ligation assay (PLA) and immunoprecipitation studies confirm GLUT1 interaction with TUBB4. Treatment of GSC33 and GSC28 cells with TUBB4 inhibitor, CR-42-24, reduces the expression of GLUT1 however, TUBB4 expression is unaltered upon fasentin treatment. Using human pluripotent stem cell antibody array, we demonstrate reduced levels of Oct3/4, Nanog, Sox2, Sox17, Snail and VEGFR2 (Vascular endothelial growth factor receptor 2) upon CR-42-24 treatment. Overall, our data confirm that silencing TUBB4 or GLUT1 reduce GSC tumorsphere formation, self-renewal and proliferation in vitro. These findings suggest GLUT1 and its binding partner TUBB4 as druggable targets that warrant further investigation in GBM.
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spelling pubmed-67711322019-10-30 GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets Guda, Maheedhara R. Labak, Collin M. Omar, Sara Ibrahim Asuthkar, Swapna Airala, Subra Tuszynski, Jack Tsung, Andrew J. Velpula, Kiran K. Cancers (Basel) Article Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor, portending a median 13-month survival even following gross total resection with adjuvant chemotherapy and radiotherapy. This prognosis necessitates improved therapies for the disease. A target of interest for novel chemotherapies is the Warburg Effect, which describes the tumor’s shift away from oxidative phosphorylation towards glycolysis. Here, we elucidate GLUT1 (Glucose transporter 1) and one of its associated binding partners, TUBB4 (Tubulin 4), as potentially druggable targets in GBM. Using data mining approach, we demonstrate that GLUT1 is overexpressed as a function of tumor grade in astrocytoma’s and that its overexpression is associated with poorer prognosis. Using both mass spectrometry performed on hGBM (human glioblastoma patient specimen) and in silico modeling, we show that GLUT1 interacts with TUBB4, and more accurately demonstrates GLUT1’s binding with fasentin. Proximity ligation assay (PLA) and immunoprecipitation studies confirm GLUT1 interaction with TUBB4. Treatment of GSC33 and GSC28 cells with TUBB4 inhibitor, CR-42-24, reduces the expression of GLUT1 however, TUBB4 expression is unaltered upon fasentin treatment. Using human pluripotent stem cell antibody array, we demonstrate reduced levels of Oct3/4, Nanog, Sox2, Sox17, Snail and VEGFR2 (Vascular endothelial growth factor receptor 2) upon CR-42-24 treatment. Overall, our data confirm that silencing TUBB4 or GLUT1 reduce GSC tumorsphere formation, self-renewal and proliferation in vitro. These findings suggest GLUT1 and its binding partner TUBB4 as druggable targets that warrant further investigation in GBM. MDPI 2019-09-05 /pmc/articles/PMC6771132/ /pubmed/31491891 http://dx.doi.org/10.3390/cancers11091308 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Guda, Maheedhara R.
Labak, Collin M.
Omar, Sara Ibrahim
Asuthkar, Swapna
Airala, Subra
Tuszynski, Jack
Tsung, Andrew J.
Velpula, Kiran K.
GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets
title GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets
title_full GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets
title_fullStr GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets
title_full_unstemmed GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets
title_short GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets
title_sort glut1 and tubb4 in glioblastoma could be efficacious targets
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771132/
https://www.ncbi.nlm.nih.gov/pubmed/31491891
http://dx.doi.org/10.3390/cancers11091308
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