4.3 Article

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

期刊

ONCOTARGET
卷 7, 期 45, 页码 73414-73431

出版社

IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12337

关键词

glioblastoma; CSCs; epithelial-mesenchymal transition; choline metabolism; choline kinase alpha

资金

  1. Friedrich-Ebert Stiftung
  2. SFF Grants of the HHU University, Duesseldorf, Germany, [701 301 640]
  3. Duesseldorf School of Oncology
  4. Comprehensive Cancer Center Duesseldorf/Deutsche Krebshilfe
  5. Medical Faculty HHU Duesseldorf

向作者/读者索取更多资源

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 (H-1 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 (CHK alpha) 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 CHK alpha inhibitor V-11-0711. Taken together, specific inhibition of the enzymatic activity of CHK alpha 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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