Castration-resistant prostate cancer (CRPC) has become a significant problem in the current treatment of prostate cancer (PCa) with the characteristics of high metastatic potential, resistance and easy recurrence. The abnormal activation of JAK2/STAT3/MCL-1 and NF-κB has been confirmed as the main reason for the development of CRPC. We previously found that β-elemonic acid (β-EA) as a natural triterpene has potential anti-inflammatory and anti-osteosarcoma effects with lower toxicity. But it remains unknown whether it had effects on CRPC. The present research in vitro and in vivo systematically investigates anti-cancer effects and mechanisms of β-EA on human CRPC. β-EA treatment resulted in apoptotic cell death in human PCa cells by mitochondrial apoptotic pathways (including up-regulation of cleaved caspase-3, cleaved PARP, and Bax or down-regulation of Bcl-2). Besides, β-EA at relatively lower levels inhibited colony-forming, the migration and invasion potential of PCa cells, indicating its anti-proliferation and anti-metastasis activities. After exploring the potential mechanism, our results suggested that it subsequently inhibited the activation of JAK2/STAT3/MCL-1 and NF-κB signaling pathway by the administration of β-EA. The silencing of NF-κB/p65, JAK2 and STAT3, respectively, increased the sensitivity of the PCa cells to β-EA induced apoptosis. Moreover, β-EA exhibited a strong affinity with its essential proteins JAK2, RELA/p65, NF-κBIα/IκBα by molecular docking analysis. Importantly, β-EA retards tumor growth in a murine xenograft model, consistent with our study in vitro. Taken together, findings from this study reveal for the first time the potential role and mechanisms of β-EA on CRPC.

在当前的前列腺癌（PCa）治疗中，去势抵抗性前列腺癌（CRPC）具有高转移潜能，耐药性和易复发的特点，已成为一个重大问题。已经证实JAK2 / STAT3 / MCL-1和NF-κB的异常激活是CRPC发生的主要原因。我们先前发现，β-柠檬酸（β-EA）作为天然三萜具有潜在的抗炎和抗骨肉瘤作用，且毒性较低。但是，它是否对CRPC产生影响仍然未知。本研究在体外和体内系统地研究了β-EA对人CRPC的抗癌作用及其机制。β-EA处理通过线粒体凋亡途径（包括裂解的caspase-3，PARP裂解和Bax上调或Bcl-2的下调）导致人PCa细胞凋亡。此外，相对较低水平的β-EA抑制PCa细胞的集落形成，迁移和侵袭能力，表明其具有抗增殖和抗转移活性。在探索潜在的机制后，我们的结果表明，其随后通过施用β-EA抑制了JAK2 / STAT3 / MCL-1和NF-κB信号通路的激活。NF-κB/ p65，JAK2和STAT3的沉默分别增加了PCa细胞对β-EA诱导的细胞凋亡的敏感性。而且，通过分子对接分析，β-EA与必需蛋白JAK2，RELA / p65，NF-κBIα/IκBα具有很强的亲和力。重要的是，在我们的小鼠异种移植模型中，β-EA会延迟肿瘤的生长，这与我们的研究一致体外。两者合计，这项研究的发现首次揭示了β-EA在CRPC中的潜在作用和机制。