Abstract
Background. The transcription factor NF-kappa B drives neoplastic progression of many cancers including primary brain tumors (glioblastoma [GBM]). Precise therapeutic modulation of NF-kappa B activity can suppress central oncogenic signaling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive. Methods. In a pharmacogenomics study with a panel of transgenic glioma cells, we observed that NF-kappa B can be converted into a tumor suppressor by the non-psychotropic cannabinoid cannabidiol (CBD). Subsequently, we investigated the anti-tumor effects of CBD, which is used as an anticonvulsive drug (Epidiolex) in pediatric neurology, in a larger set of human primary GBM stem-like cells (hGSC). For this study, we performed pharmacological assays, gene expression profiling, biochemical, and cell-biological experiments. We validated our findings using orthotopic in vivo models and bioinformatics analysis of human GBM datasets. Results. We found that CBD promotes DNA binding of the NF-kappa B subunit RELA and simultaneously prevents RELA phosphorylation on serine-311, a key residue that permits genetic transactivation. Strikingly, sustained DNA binding by RELA-lacking phospho-serine 311 was found to mediate hGSC cytotoxicity. Widespread sensitivity to CBD was observed in a cohort of hGSC defined by low levels of reactive oxygen species (ROS), while high ROS content in other tumors blocked CBD-induced hGSC death. Consequently, ROS levels served as a predictive biomarker for CBD-sensitive tumors. Conclusions. This evidence demonstrates how a clinically approved drug can convert NF-kappa B into a tumor suppressor and suggests a promising repurposing option for GBM therapy.
Dokumententyp: | Zeitschriftenartikel |
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Fakultät: | Medizin |
Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
ISSN: | 1522-8517 |
Sprache: | Englisch |
Dokumenten ID: | 102847 |
Datum der Veröffentlichung auf Open Access LMU: | 05. Jun. 2023, 15:41 |
Letzte Änderungen: | 17. Okt. 2023, 15:12 |