Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, 676 N St. Clair, Suite 2210, Chicago, IL, 60611, USA.
Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Sci Rep. 2024 Sep 20;14(1):21959. doi: 10.1038/s41598-024-73051-1.
Glioblastoma is a Grade 4 primary brain tumor defined by therapy resistance, diffuse infiltration, and near-uniform lethality. The underlying mechanisms are unknown, and no treatment has been curative. Using a recently developed creatine kinase inhibitor (CKi), we explored the role of this inhibitor on GBM biology in vitro. While CKi minimally impacted GBM cell proliferation and viability, it significantly affected migration. In established GBM cell lines and patient-derived xenografts, CKi ablated both the migration and invasion of GBM cells. CKi also hindered radiation-induced migration. RNA-seq revealed a decrease in invasion-related genes, with an unexpected increase in glutathione metabolism and ferroptosis protection genes post-CKi treatment. The effects of CKi could be reversed by the addition of cell-permeable glutathione. Carbon-13 metabolite tracing indicated heightened glutathione biosynthesis post-CKi treatment. Combinatorial CKi blockade and glutathione inhibition or ferroptosis activation abrogated cell survival. Our data demonstrated that CKi perturbs promigratory and anti-ferroptotic roles in GBM, identifying the creatine kinase axis as a druggable target for GBM treatment.
胶质母细胞瘤是一种 4 级原发性脑肿瘤，其特征为对治疗有抵抗力、弥漫性浸润和近乎一致的致死性。其潜在机制尚不清楚，也没有治疗方法是根治性的。我们使用最近开发的肌酸激酶抑制剂（CKi），在体外探索了这种抑制剂对 GBM 生物学的作用。虽然 CKi 对 GBM 细胞的增殖和活力影响很小，但它显著影响了迁移。在已建立的 GBM 细胞系和患者来源的异种移植物中，CKi 消除了 GBM 细胞的迁移和侵袭。CKi 还阻碍了放射诱导的迁移。RNA-seq 显示侵袭相关基因减少，而 CKi 治疗后谷胱甘肽代谢和铁死亡保护基因意外增加。CKi 的作用可以通过添加可渗透细胞的谷胱甘肽来逆转。碳 13 代谢物追踪表明 CKi 治疗后谷胱甘肽生物合成增加。组合 CKi 阻断和谷胱甘肽抑制或铁死亡激活消除了细胞存活。我们的数据表明，CKi 扰乱了 GBM 中的促迁移和抗铁死亡作用，确定肌酸激酶轴为 GBM 治疗的可用药靶标。
