Neurosurgical Research, Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany.
Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Neuro Oncol. 2021 Nov 2;23(11):1898-1910. doi: 10.1093/neuonc/noab095.
The transcription factor NF-κB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma [GBM]). Precise therapeutic modulation of NF-κB activity can suppress central oncogenic signaling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive.
In a pharmacogenomics study with a panel of transgenic glioma cells, we observed that NF-κB 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.
We found that CBD promotes DNA binding of the NF-κB 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.
This evidence demonstrates how a clinically approved drug can convert NF-κB into a tumor suppressor and suggests a promising repurposing option for GBM therapy.
转录因子 NF-κB 驱动包括原发性脑肿瘤（胶质母细胞瘤[GBM]）在内的许多癌症的肿瘤进展。NF-κB 活性的精确治疗调节可以抑制 GBM 中的中枢致癌信号通路，但仍难以找到用于实现这一目标的临床适用化合物。
在一组转基因神经胶质瘤细胞的药物基因组学研究中，我们观察到 NF-κB 可以被非精神活性大麻素大麻二酚（CBD）转化为肿瘤抑制因子。随后，我们研究了 CBD 的抗肿瘤作用，CBD 作为一种抗惊厥药物（Epidiolex）在儿科神经病学中使用，在更大的一组人原发性 GBM 干细胞样细胞（hGSC）中。为此研究，我们进行了药理学测定、基因表达谱分析、生化和细胞生物学实验。我们使用原位体内模型和人类 GBM 数据集的生物信息学分析验证了我们的发现。
我们发现 CBD 促进 NF-κB 亚基 RELA 的 DNA 结合，同时阻止 RELA 在丝氨酸 311 上的磷酸化，这是允许遗传转录激活的关键残基。引人注目的是，发现缺乏磷酸丝氨酸 311 的 RELA 的持续 DNA 结合介导 hGSC 细胞毒性。在一组由低水平活性氧（ROS）定义的 hGSC 中观察到对 CBD 的广泛敏感性，而其他肿瘤中的高 ROS 含量阻止了 CBD 诱导的 hGSC 死亡。因此，ROS 水平作为 CBD 敏感肿瘤的预测生物标志物。
该证据表明，一种临床批准的药物如何将 NF-κB 转化为肿瘤抑制因子，并为 GBM 治疗提供了一种有前途的重新定位选择。
