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Identification of berberine as a novel drug for the treatment of multiple myeloma via targeting UHRF1
BMC Biology ( IF 5.4 ) Pub Date : 2020-03-25 , DOI: 10.1186/s12915-020-00766-8
Chunming Gu , Zhao Yin , Hong Nie , Yanjun Liu , Juhua Yang , Guiping Huang , Jianping Shen , Liguo Chen , Jia Fei

Current therapies for multiple myeloma (MM) are associated with toxicity and resistance, highlighting the need for novel effective therapeutics. Berberine (BBR), a botanical alkaloid derived from several Berberis medicinal plants, has exhibited anti-tumor effects, including against multiple myeloma (MM); however, the molecular mechanism underlying the anti-MM effect has not been previously described. This study aimed to identify the target of berberine and related mechanisms involved in its therapeutic activity against MM. Here, we demonstrated that BBR treatment killed MM cells in vitro and prolonged the survival of mice bearing MM xenografts in vivo. A screening approach integrating surface plasmon resonance (SPR) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified UHRF1 (ubiquitin-like with PHD and RING Finger domains 1) as a potential target of BBR. Combining molecular docking and SPR analysis, we confirmed UHRF1 as a BBR-binding protein and discovered that BBR binds UHRF1 in the tandem tudor domain and plant homeodomain (TTD-PHD domain). BBR treatment induced UHRF1 degradation via the ubiquitin-dependent proteasome system and reactivated p16INK4A and p73 in MM cells. Overexpression of UHRF1 promoted the MM cell proliferation and rendered MM cells more resistant to BBR, while silencing of UHRF1 with siRNA attenuated BBR-induced cytotoxicity. In summary, our study has identified UHRF1 as a direct target of BBR and uncovered molecular mechanisms involved in the anti-MM activity of BBR. Targeting UHRF1 through BBR may be a novel therapeutic strategy against MM.

中文翻译:

小targeting碱作为靶向UHRF1的多发性骨髓瘤治疗新药的鉴定

多发性骨髓瘤(MM)的当前疗法与毒性和耐药性有关,突出了对新型有效疗法的需求。小ber碱(BBR)是一种源自多种小Ber药用植物的植物生物碱,具有抗肿瘤作用,包括抗多发性骨髓瘤(MM)。然而,先前尚未描述抗MM作用的分子机制。这项研究旨在确定小ber碱的靶标及其参与对MM的治疗活性的相关机制。在这里,我们证明了BBR处理可在体外杀死MM细胞,并延长了携带MM异种移植物的小鼠的体内存活。结合表面等离子体激元共振(SPR)和液相色谱-串联质谱(LC-MS / MS)的筛选方法将UHRF1(泛素样蛋白具有PHD和RING Finger域1)确定为BBR的潜在靶标。结合分子对接和SPR分析,我们确认UHRF1是BBR结合蛋白,并发现BBR在串联tudor域和植物同源域(TTD-PHD域)中结合UHRF1。BBR处理可通过泛素依赖性蛋白酶体系统诱导UHRF1降解,并在MM细胞中重新激活p16INK4A和p73。UHRF1的过表达促进MM细胞增殖,并使MM细胞对BBR更具有抵抗力,而用siRNA沉默UHRF1则减弱了BBR诱导的细胞毒性。综上所述,我们的研究确定UHRF1是BBR的直接靶点,并且未发现参与BBR抗MM活性的分子机制。通过BBR靶向UHRF1可能是针对MM的新型治疗策略。
更新日期:2020-04-22
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