title: Reciprocal regulation of the cholinic phenotype and epithelial-mesenchymal transition in glioblastoma cells.
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.
authors.affiliation: Neurosurgery Department, University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Koch
authors.affiliation: Institute of Complex Systems (ICS-6) Structural Biochemistry, Forschungszentrum Juelich, Juelich, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Hartmann
authors.affiliation: Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Schröter
authors.affiliation: Neurosurgery Department, University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Abigail Kora
authors.initials: AK
authors.lastname: Suwala
authors.affiliation: Neurosurgery Department, University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Donata
authors.initials: D
authors.lastname: Maciaczyk
authors.affiliation: Neurosurgery Department, University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Andrea Caroline
authors.initials: AC
authors.lastname: Krüger
authors.affiliation: Institute of Complex Systems (ICS-6) Structural Biochemistry, Forschungszentrum Juelich, Juelich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
authors.affiliation: Neurosurgery Department, University Hospital Duesseldorf, Duesseldorf, Germany.|Neurosurgery and Pediatric Neurosurgery, Medical University Lublin, Lublin, Poland.
authors.forename: Ulf Dietrich
authors.initials: UD
authors.lastname: Kahlert
authors.affiliation: Neurosurgery Department, University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Maciaczyk
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002794:Choline / Q000378:metabolism*; D002797:Choline Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004734:Energy Metabolism / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010641:Phenotype; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D000077204:Temozolomide; D014746:Vimentin / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics
chemical_list: C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014746:Vimentin; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D003606:Dacarbazine; C517212:CHKA protein, human; D002797:Choline Kinase; D002794:Choline; D000077204:Temozolomide
keywords: CSCs; choline kinase alpha; choline metabolism; epithelial-mesenchymal transition; glioblastoma