Oncotarget

Research Papers:

Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells

Katharina Koch, Rudolf Hartmann, Friederike Schröter, Abigail Kora Suwala, Donata Maciaczyk, Andrea Caroline Krüger, Dieter Willbold, Ulf Dietrich Kahlert and Jaroslaw Maciaczyk _

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Oncotarget. 2016; 7:73414-73431. https://doi.org/10.18632/oncotarget.12337

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Abstract

Katharina Koch1, Rudolf Hartmann2, Friederike Schröter3, Abigail Kora Suwala1, Donata Maciaczyk1, Andrea Caroline Krüger1, Dieter Willbold2,4, Ulf Dietrich Kahlert1,5, Jaroslaw Maciaczyk1

1Neurosurgery Department, University Hospital Duesseldorf, Duesseldorf, Germany

2Institute of Complex Systems (ICS-6) Structural Biochemistry, Forschungszentrum Juelich, Juelich, Germany

3Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany

4Institut für Physikalische Biologie, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany

5Neurosurgery and Pediatric Neurosurgery, Medical University Lublin, Lublin, Poland

Correspondence to:

Jaroslaw Maciaczyk, email: [email protected]

Keywords: glioblastoma, CSCs, epithelial-mesenchymal transition, choline metabolism, choline kinase alpha

Received: May 26, 2016     Accepted: September 19, 2016     Published: September 29, 2016

ABSTRACT

Glioblastoma (GBM) is the most malignant brain tumor with very limited therapeutic options. Standard multimodal treatments, including surgical resection and combined radio-chemotherapy do not target the most aggressive subtype of glioma cells, brain tumor stem cells (BTSCs). BTSCs are thought to be responsible for tumor initiation, progression, and relapse. Furthermore, they have been associated with the expression of mesenchymal features as a result of epithelial-mesenchymal transition (EMT) thereby inducing tumor dissemination and chemo resistance. Using high resolution proton nuclear magnetic resonance spectroscopy (1H NMR) on GBM cell cultures we provide evidence that the expression of well-known EMT activators of the ZEB, TWIST and SNAI families and EMT target genes N-cadherin and VIMENTIN is associated with aberrant choline metabolism. The cholinic phenotype is characterized by high intracellular levels of phosphocholine and total choline derivatives and was associated with malignancy in various cancers. Both genetic and pharmacological inhibition of the cardinal choline metabolism regulator choline kinase alpha (CHKα) significantly reduces the cell viability, invasiveness, clonogenicity, and expression of EMT associated genes in GBM cells. Moreover, in some cell lines synergetic cytotoxic effects were observed when combining the standard of care chemotherapeutic temozolomide with the CHKα inhibitor V-11-0711. Taken together, specific inhibition of the enzymatic activity of CHKα is a powerful strategy to suppress EMT which opens the possibility to target chemo-resistant BTSCs through impairing their mesenchymal transdifferentiation. Moreover, the newly identified EMT-oncometabolic network may be helpful to monitor the invasive properties of glioblastomas and the success of anti-EMT therapy.


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