We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy.
- Authors
Helweg, Laureen P.; Storm, Jonathan; Witte, Kaya E.; Schulten, Wiebke; Wrachtrup, Lennart; Janotte, Till; Kitke, Angelika; Greiner, Johannes F. W.; Knabbe, Cornelius; Kaltschmidt, Barbara; Simon, Matthias; Kaltschmidt, Christian
- Abstract
Glioblastoma multiforme (GBM) is the most aggressive and most common malignant brain tumor with poor patient survival despite therapeutic intervention. On the cellular level, GBM comprises a rare population of glioblastoma stem cells (GSCs), driving therapeutic resistance, invasion, and recurrence. GSCs have thus come into the focus of therapeutic strategies, although their targeting remains challenging. In the present study, we took advantage of three GSCs-populations recently established in our lab to investigate key signaling pathways and subsequent therapeutic strategies targeting GSCs. We observed that NF-κB, a crucial transcription factor in GBM progression, was expressed in all CD44+/CD133+/Nestin+-GSC-populations. Exposure to TNFα led to activation of NF-κB-RELA and/or NF-κB-c-REL, depending on the GBM type. GSCs further expressed the proto-oncogene MYC family, with MYChigh GSCs being predominantly located in the tumor spheres ("GROW"-state) while NF-κB-RELAhigh GSCs were migrating out of the sphere ("GO"-state). We efficiently targeted GSCs by the pharmacologic inhibition of NF-κB using PTDC/Bortezomib or inhibition of MYC by KJ-Pyr-9, which significantly reduced GSC-viability, even in comparison to the standard chemotherapeutic drug temozolomide. As an additional cell-therapeutic strategy, we showed that NK cells could kill GSCs. Our findings offer new perspectives for developing efficient patient-specific chemo- and immunotherapy against GBM.
- Subjects
STEM cells; CELLULAR signal transduction; BRAIN tumors; GLIOBLASTOMA multiforme; KILLER cells
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 21, p12919
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms232112919