Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China.
Br J Pharmacol. 2023 Dec;180(24):3175-3193. doi: 10.1111/bph.16202. Epub 2023 Aug 22.
Osteosarcoma, a primary malignant bone tumour prevalent among adolescents and young adults, remains a considerable challenge despite protracted progress made in enhancing patient survival rates over the last 40 years. Consequently, the development of novel therapeutic approaches for osteosarcoma is imperative. Sanguinarine (SNG), a compound with demonstrated potent anticancer properties against various malignancies, presents a promising avenue for exploration. Nevertheless, the intricate molecular mechanisms underpinning SNG's actions in osteosarcoma remain elusive, necessitating further elucidation.
Single-stranded DNA-binding protein 1 (SSBP1) was screened out by differential proteomic analysis. Apoptosis, cell cycle, reactive oxygen species (ROS) and mitochondrial changes were assessed via flow cytometry. Western blotting and quantitative real-time reverse transcription PCR (qRT-PCR) were used to determine protein and gene levels. The antitumour mechanism of SNG was explored at a molecular level using chromatin immunoprecipitation (ChIP) and dual luciferase reporter plasmids.
Our investigation revealed that SNG exerted an up-regulated effect on SSBP1, disrupting mitochondrial function and inducing apoptosis. In-depth analysis uncovered a mechanism whereby SNG hindered the JAK/signal transducer and activator of transcription 3 (STAT3) signalling pathway, relieved the inhibitory effect of STAT3 on SSBP1 transcription, and inhibited the downstream PI3K/Akt/mTOR signalling axis, ultimately activating apoptosis.
The study delved further into elucidating the anticancer mechanism of SNG in osteosarcoma. Notably, we unravelled the previously undisclosed apoptotic potential of SSBP1 in osteosarcoma cells. This finding holds substantial promise in advancing the development of novel anticancer drugs and identification of therapeutic targets.
骨肉瘤是一种常见于青少年和年轻人的原发性恶性骨肿瘤，尽管在过去 40 年中，提高患者生存率方面取得了长足的进展，但它仍然是一个巨大的挑战。因此，开发治疗骨肉瘤的新方法势在必行。血根碱（SNG）是一种对多种恶性肿瘤具有显著抗癌作用的化合物，为探索提供了一个有前途的途径。然而，SNG 作用于骨肉瘤的复杂分子机制仍不清楚，需要进一步阐明。
通过差异蛋白质组学分析筛选出单链 DNA 结合蛋白 1（SSBP1）。通过流式细胞术评估细胞凋亡、细胞周期、活性氧（ROS）和线粒体变化。使用 Western blot 和定量实时逆转录 PCR（qRT-PCR）测定蛋白和基因水平。使用染色质免疫沉淀（ChIP）和双荧光素酶报告质粒从分子水平探讨 SNG 的抗肿瘤机制。
我们的研究表明 SNG 对 SSBP1 具有上调作用，破坏线粒体功能并诱导细胞凋亡。深入分析揭示了 SNG 抑制 JAK/信号转导和转录激活因子 3（STAT3）信号通路的机制，减轻了 STAT3 对 SSBP1 转录的抑制作用，并抑制了下游 PI3K/Akt/mTOR 信号轴，最终激活细胞凋亡。
本研究进一步阐明了 SNG 在骨肉瘤中的抗癌机制。值得注意的是，我们揭示了 SSBP1 在骨肉瘤细胞中以前未被发现的凋亡潜力。这一发现为开发新型抗癌药物和鉴定治疗靶点提供了巨大的潜力。
