Longikaurin A induces ferroptosis and inhibits glioblastoma progression through DNA methylation - Mediated GPX4 suppression

• Published in: European journal of pharmacology 2024-12, Vol.984, p.177061, Article 177061
• Main Authors: Meng, Xiangrui, Yang, Qingqing, Gao, Yisu, Liu, Yawei, Chen, Fang, Cao, Wangsen, Sun, Guan
• Format: Article
• Language: English
• Subjects: Animals; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Cell Line, Tumor; CpG Islands - drug effects; CpG Islands - genetics; Dioxygenases - genetics; Disease Progression; Diterpenes - pharmacology; Diterpenes - therapeutic use; DNA methylation; DNA Methylation - drug effects; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Ferroptosis; Ferroptosis - drug effects; Ferroptosis - genetics; Gene Expression Regulation, Neoplastic - drug effects; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - pathology; GPX4; Humans; LongikaurinA; Mice; Mice, Nude; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Promoter Regions, Genetic - drug effects; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2024.177061

Glioblastoma (GBM) is the most common primary intracranial tumor highly resistant to conventional clinical chemotherapy. Recently, the induction of ferroptosis is emerging as a putative strategy to treat various tumors. However, the identification of the effective and applicable tumor ferroptosis-inducing agents remains challenging. In this study, we showed that longikaurin A (LK-A), a natural diterpenoid isolated from the medicinal plant Isodon ternifolius with strong anti-GBM capacities, induced remarkable GBM cell ferroptosis along with suppressing the key anti-ferroptosis factor glutathione peroxidase 4 (GPX4). GPX4 promoter contains conserved CpG islands. The LK-A-induced GPX4 suppression coincided with the inhibition of ten-eleven translocation 2 (TET2), a key DNA demethylation enzyme and an increase in the hypermethylation of the GPX4 promoter. Further, LK-A promoted the GBM ferroptotic alterations and inhibited GBM progression in both subcutaneous and orthotopic xenograft mouse models, whereas GPX4 overexpression largely abrogated its anti-GBM effects both in vitro and in vivo, suggesting that LK-A inductions of the DNA methylation-incurred GPX4 suppression and ferroptosis are crucial for its anti-GBM functions. Together, our study has elaborated an important epigenetic pathway of GBM ferroptosis and uncovered a critical pharmacological property of LK-A for treating GBM patients. A schematic diagram of LK-A-induced GBM ferroptosis. LK-A inhibits TET2 expression, consequentially induces GPX4 promoter hypermethylation and GPX4 transcriptional suppression, resulting in increased lipid peroxidation and GBM ferroptosis. [Display omitted]