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Int J Mol Sci. 2018 Jul 25;19(8). pii: E2168. doi: 10.3390/ijms19082168.

Gene Suppression of Transketolase-Like Protein 1 (TKTL1) Sensitizes Glioma Cells to Hypoxia and Ionizing Radiation.

Heller S1,2, Maurer GD3,4, Wanka C5,6, Hofmann U7, Luger AL8,9, Bruns I10,11, Steinbach JP12,13, Rieger J14,15,16.

Author information

1
Dr. Senckenberg Institute of Neurooncology and University Cancer Center (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany. sonja.heller@kgu.de.
2
German Cancer Research Center (DKFZ) Heidelberg, German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany. sonja.heller@kgu.de.
3
Dr. Senckenberg Institute of Neurooncology and University Cancer Center (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany. gabriele.maurer@kgu.de.
4
German Cancer Research Center (DKFZ) Heidelberg, German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany. gabriele.maurer@kgu.de.
5
Dr. Senckenberg Institute of Neurooncology and University Cancer Center (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany. christina.wanka@gmx.de.
6
German Cancer Research Center (DKFZ) Heidelberg, German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany. christina.wanka@gmx.de.
7
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Eberhard Karls University, 72074 Tuebingen, Germany. ute.hofmann@ikp-stuttgart.de.
8
Dr. Senckenberg Institute of Neurooncology and University Cancer Center (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany. anna-luisa.luger@kgu.de.
9
German Cancer Research Center (DKFZ) Heidelberg, German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany. anna-luisa.luger@kgu.de.
10
Dr. Senckenberg Institute of Neurooncology and University Cancer Center (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany. i.hartel@web.de.
11
German Cancer Research Center (DKFZ) Heidelberg, German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany. i.hartel@web.de.
12
Dr. Senckenberg Institute of Neurooncology and University Cancer Center (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany. joachim.steinbach@med.uni-frankfurt.de.
13
German Cancer Research Center (DKFZ) Heidelberg, German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany. joachim.steinbach@med.uni-frankfurt.de.
14
Dr. Senckenberg Institute of Neurooncology and University Cancer Center (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany. j.rieger@uni-tuebingen.de.
15
German Cancer Research Center (DKFZ) Heidelberg, German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany. j.rieger@uni-tuebingen.de.
16
Interdisciplinary Division of Neuro-Oncology, Hertie Institute for Clinical Brain Research, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, Germany. j.rieger@uni-tuebingen.de.

Abstract

In several tumor entities, transketolase-like protein 1 (TKTL1) has been suggested to promote the nonoxidative part of the pentose phosphate pathway (PPP) and thereby to contribute to a malignant phenotype. However, its role in glioma biology has only been sparsely documented. In the present in vitro study using LNT-229 glioma cells, we analyzed the impact of TKTL1 gene suppression on basic metabolic parameters and on survival following oxygen restriction and ionizing radiation. TKTL1 was induced by hypoxia and by hypoxia-inducible factor-1α (HIF-1α). Knockdown of TKTL1 via shRNA increased the cells' demand for glucose, decreased flux through the PPP and promoted cell death under hypoxic conditions. Following irradiation, suppression of TKTL1 expression resulted in elevated levels of reactive oxygen species (ROS) and reduced clonogenic survival. In summary, our results indicate a role of TKTL1 in the adaptation of tumor cells to oxygen deprivation and in the acquisition of radioresistance. Further studies are necessary to examine whether strategies that antagonize TKTL1 function will be able to restore the sensitivity of glioma cells towards irradiation and antiangiogenic therapies in the more complex in vivo environment.

KEYWORDS:

glioma; hypoxia; metabolism; pentose phosphate pathway; radiation; transketolase-like protein 1

PMID:
30044385
PMCID:
PMC6121283
DOI:
10.3390/ijms19082168
[Indexed for MEDLINE]
Free PMC Article

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