2-羟基-3-甲基蒽醌通过 MYC-CHK1-RAD51 轴抑制骨肉瘤的同源重组修复。
2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis.
机构信息
Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China.
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
出版信息
Mol Med. 2023 Jan 30;29(1):15. doi: 10.1186/s10020-023-00611-y.
BACKGROUND
Osteosarcoma is a malignant bone tumor that usually affects adolescents aged 15-19 y. The DNA damage response (DDR) is significantly enhanced in osteosarcoma, impairing the effect of systemic chemotherapy. Targeting the DDR process was considered a feasible strategy benefitting osteosarcoma patients. However, the clinical application of DDR inhibitors is not impressive because of their side effects. Chinese herbal medicines with high anti-tumor effects and low toxicity in the human body have gradually gained attention. 2-Hydroxy-3-methylanthraquinone (HMA), a Chinese medicine monomer found in the extract of Oldenlandia diffusa, exerts significant inhibitory effects on various tumors. However, its anti-osteosarcoma effects and defined molecular mechanisms have not been reported.
METHODS
After HMA treatment, the proliferation and metastasis capacity of osteosarcoma cells was detected by CCK-8, colony formation, transwell assays and Annexin V-fluorescein isothiocyanate/propidium iodide staining. RNA-sequence, plasmid infection, RNA interference, Western blotting and immunofluorescence assay were used to investigate the molecular mechanism and effects of HMA inhibiting osteosarcoma. Rescue assay and CHIP assay was used to further verified the relationship between MYC, CHK1 and RAD51.
RESULTS
HMA regulate MYC to inhibit osteosarcoma proliferation and DNA damage repair through PI3K/AKT signaling pathway. The results of RNA-seq, IHC, Western boltting etc. showed relationship between MYC, CHK1 and RAD51. Rescue assay and CHIP assay further verified HMA can impair homologous recombination repair through the MYC-CHK1-RAD51 pathway.
CONCLUSION
HMA significantly inhibits osteosarcoma proliferation and homologous recombination repair through the MYC-CHK1-RAD51 pathway, which is mediated by the PI3K-AKT signaling pathway. This study investigated the exact mechanism of the anti-osteosarcoma effect of HMA and provided a potential feasible strategy for the clinical treatment of human osteosarcoma.
背景
骨肉瘤是一种常见于 15-19 岁青少年的恶性骨肿瘤。骨肉瘤中 DNA 损伤反应（DDR）显著增强，从而削弱了全身化疗的效果。靶向 DDR 过程被认为是一种有益于骨肉瘤患者的可行策略。然而，由于 DDR 抑制剂的副作用，其临床应用并不理想。具有高抗肿瘤作用和低毒性的中草药在人体内逐渐受到关注。2-羟基-3-甲基蒽醌（HMA）是从白花蛇舌草提取物中发现的一种中药单体，对各种肿瘤均有显著的抑制作用。然而，其抗骨肉瘤作用及其明确的分子机制尚未报道。
方法
用 CCK-8、集落形成、Transwell 检测和 Annexin V-荧光素异硫氰酸酯/碘化丙啶染色检测 HMA 处理后骨肉瘤细胞的增殖和转移能力。用 RNA 测序、质粒感染、RNA 干扰、Western blot 和免疫荧光检测来研究 HMA 抑制骨肉瘤的分子机制和作用。用挽救实验和 CHIP 实验进一步验证 MYC、CHK1 和 RAD51 之间的关系。
结果
HMA 通过 PI3K/AKT 信号通路调节 MYC 抑制骨肉瘤增殖和 DNA 损伤修复。RNA-seq、免疫组化、Western blot 等结果表明 MYC、CHK1 和 RAD51 之间存在关系。挽救实验和 CHIP 实验进一步证实 HMA 通过 MYC-CHK1-RAD51 通路损害同源重组修复。
结论
HMA 通过 MYC-CHK1-RAD51 通路显著抑制骨肉瘤增殖和同源重组修复，该通路由 PI3K-AKT 信号通路介导。本研究探讨了 HMA 抗骨肉瘤作用的确切机制，为人类骨肉瘤的临床治疗提供了一种潜在可行的策略。
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