膀胱癌是一种高发的泌尿生殖系统恶性肿瘤，其中浸润性膀胱癌（MIBC）是一种具有高死亡率的恶性肿瘤。由于现有药物存在毒性高、疗效差和副作用多等缺陷，迫切需要开发低毒性、高效性的新药物用于MIBC的治疗。已发现天然海洋化合物Jorunnamycin A（JorA）具有高效的抗癌作用，但其在膀胱癌上的抗癌功能和机制尚未研究。为了考察JorA对MIBC的抗癌作用，进行了细胞计数试剂盒8、EdU染色和克隆形成分析。此外，还使用异种移植小鼠模型验证了其体内的抗癌效果。为了研究JorA的药理机制，进行了高通量定量蛋白组学、转录组学、RT-qPCR、Western blotting、免疫荧光染色、流式细胞术、拉下实验和分子对接。JorA抑制了MIBC细胞的增殖，T24和UM-UC-3的IC50分别为0.054和0.084μM。JorA诱导的显著变化的蛋白质富集在“与癌症相关的途径”和“EGFR相关的信号通路”中，主要表现为抑制细胞增殖和促进细胞凋亡。具体而言，JorA抑制了DNA合成速率，诱导了磷脂酰丝氨酸转位，并抑制了细胞迁移。此外，还发现脂肪酸合酶（FASN）和拓扑异构酶1（TOP1）是JorA的相互作用蛋白质。通过DockThor软件获得了JorA结合到FASN和TOP1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具有特异性的对MIBC的抑制作用，并首次揭示了其潜在的药理机制。这一发现对于开发新型高效低毒性的膀胱癌治疗药物具有重要意义。© 2023. BioMed Central Ltd., part of Springer Nature.

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 IC50 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.© 2023. BioMed Central Ltd., part of Springer Nature.