Polygonum multiflorum and its active ingredient Polygalacic acid suppress lethal prostate cancer growth by inducing cell cycle arrest

The incidence of prostate cancer ranks second among cancers in men and is one of the leading causes of cancer-related death worldwide. Contemporary therapy for metastatic prostate cancer employing reagents such as AR antagonists only provides a temporary response and rapidly acquires resistance and even eventually evolves into neuroendocrine prostate cancer (NEPC), which currently with no standard therapy. Polygonum multiflorum (PM), a medicinal plant that was an element of traditional medicine for centuries worldwide, was previously reported to suppress liver cancer cell growth, while its role and mechanisms in prostate cancer remain to be explored. In this study, we reported that PM significantly suppressed the growth of prostate cancer both in vitro and in vivo, and a low dose of PM significantly sensitized prostate cancer to AR antagonists. Mechanistically, RNA-seq revealed that PM induced G2/M-phase cell-cycle arrest by modulating cell cycle-related gene activation. Additionally, we demonstrated that polygalacic acid from PM and its structural analog ursolic acid and oleanolic acid suppress prostate cancer growth by targeting CDC25B, a master regulator of the cell cycle that governs CDC2 phosphorylation, as knockdown of CDC25B with emerging CRISPR-Cas13 technology completely diminished polygalacic acid-induced cell growth inhibition. Our findings not only revealed the anti-tumor efficacy and mechanisms of PM but also demonstrated the potential benefits of combination treatment of prostate cancer with AR antagonists and traditional medicines, which dramatically increase the anti-tumor effect and may decelerate the resistance towards treatment with AR antagonists.

前列腺癌的发病率在男性恶性肿瘤中位列第二，是全球范围内引发癌症相关死亡的主要诱因之一。当前针对转移性前列腺癌的治疗方案，如雄激素受体（AR）拮抗剂类药物，仅能带来暂时性的临床应答，且肿瘤会快速产生耐药性，甚至最终进展为神经内分泌前列腺癌（NEPC），目前针对该病症尚无标准治疗策略。何首乌（Polygonum multiflorum，PM）是一种已在全球传统医学中应用逾百年的药用植物，既往研究证实其可抑制肝癌细胞增殖，但其在前列腺癌中的作用及具体机制尚待阐明。本研究结果显示，何首乌可在体外及体内显著抑制前列腺癌的生长，且低剂量的何首乌可显著增强前列腺癌细胞对AR拮抗剂的敏感性。从机制层面而言，RNA测序（RNA-seq）分析结果表明，何首乌可通过调控细胞周期相关基因的激活，诱导肿瘤细胞发生G2/M期周期阻滞。此外，本研究证实，何首乌中的远志酸（polygalacic acid）及其结构类似物熊果酸（ursolic acid）、齐墩果酸（oleanolic acid）可通过靶向细胞周期核心调控因子细胞分裂周期蛋白25B（CDC25B）发挥抑癌作用——该因子可调控细胞分裂周期蛋白2（CDC2）的磷酸化，而利用新兴的CRISPR-Cas13技术敲低CDC25B后，远志酸诱导的细胞增殖抑制作用完全消失。本研究不仅揭示了何首乌的抗肿瘤功效及其作用机制，还证实了AR拮抗剂与传统中药联合治疗前列腺癌的潜在临床价值，该联合疗法可显著增强抗肿瘤效果，并有可能延缓肿瘤对AR拮抗剂治疗的耐药性。