Medical Laboratory of Jining Medical University, Jining Medical University, Jining, 272067, Shandong, China.
Institute of Precision Medicine, Jining Medical University, No. 133 Hehua Road, Taibaihu District, Jining, 272067, Shandong, China.
J Transl Med. 2023 Aug 16;21(1):549. doi: 10.1186/s12967-023-04400-3.
Bladder cancer is a urological carcinoma with high incidence, among which muscle invasive bladder cancer (MIBC) is a malignant carcinoma with high mortality. There is an urgent need to develop new drugs with low toxicity and high efficiency for MIBC because existing medication has defects, such as high toxicity, poor efficacy, and side effects. Jorunnamycin A (JorA), a natural marine compound, has been found to have a high efficiency anticancer effect, but its anticancer function and mechanism on bladder cancer have not been studied.
To examine the anticancer effect of JorA on MIBC, Cell Counting Kit 8, EdU staining, and colony formation analyses were performed. Moreover, a xenograft mouse model was used to verify the anticancer effect in vivo. To investigate the pharmacological mechanism of JorA, high-throughput quantitative proteomics, transcriptomics, RT-qPCR, western blotting, immunofluorescence staining, flow cytometry, pulldown assays, and molecular docking were performed.
JorA inhibited the proliferation of MIBC cells, and the IC of T24 and UM-UC-3 was 0.054 and 0.084 μM, respectively. JorA-induced significantly changed proteins were enriched in "cancer-related pathways" and "EGFR-related signaling pathways", which mainly manifested by inhibiting cell proliferation and promoting cell apoptosis. Specifically, JorA dampened the DNA synthesis rate, induced phosphatidylserine eversion, and inhibited cell migration. Furthermore, it was discovered that fatty acid synthase (FASN) and topoisomerase 1 (TOP1) are the JorA interaction proteins. Using DockThor software, the 3D docking structures of JorA binding to FASN and TOP1 were obtained (the binding affinities were - 8.153 and - 7.264 kcal/mol, respectively).
The marine compound JorA was discovered to have a specific inhibitory effect on MIBC, and its potential pharmacological mechanism was revealed for the first time. This discovery makes an important contribution to the development of new high efficiency and low toxicity drugs for bladder cancer therapy.
膀胱癌是一种发病率较高的泌尿系统癌，其中肌层浸润性膀胱癌（MIBC）是一种死亡率较高的恶性癌。由于现有药物存在毒性高、疗效差、副作用大等缺陷，迫切需要开发低毒性、高效的 MIBC 新药。乔拉霉素 A（JorA）是一种天然海洋化合物，已被发现具有高效的抗癌作用，但它在膀胱癌中的抗癌作用和机制尚未得到研究。
为了研究 JorA 对 MIBC 的抗癌作用，采用细胞计数试剂盒 8、EdU 染色和集落形成分析进行检测。此外，还使用异种移植小鼠模型在体内验证了抗癌作用。为了研究 JorA 的药理机制，进行了高通量定量蛋白质组学、转录组学、RT-qPCR、western blot、免疫荧光染色、流式细胞术、下拉实验和分子对接。
JorA 抑制 MIBC 细胞增殖，T24 和 UM-UC-3 的 IC 分别为 0.054 和 0.084 μM。JorA 诱导的显著变化蛋白富集在“癌症相关途径”和“EGFR 相关信号通路”中，主要表现为抑制细胞增殖和促进细胞凋亡。具体而言，JorA 降低了 DNA 合成率，诱导了磷脂酰丝氨酸外翻，并抑制了细胞迁移。此外，发现脂肪酸合酶（FASN）和拓扑异构酶 1（TOP1）是 JorA 的相互作用蛋白。使用 DockThor 软件，获得了 JorA 与 FASN 和 TOP1 结合的 3D 对接结构（结合亲和力分别为-8.153 和-7.264 kcal/mol）。
发现海洋化合物 JorA 对 MIBC 具有特异性抑制作用，首次揭示了其潜在的药理机制。这一发现为开发高效低毒的膀胱癌治疗新药做出了重要贡献。
