中国科学院在生物毒素成分抑制肿瘤生长研究中取得进展

2022-07-01 中国科学院 网络

香豆素β在体内对骨肉瘤具有良好的抑制效果,并且没有明显的系统毒性。

骨肉瘤是一种常见于青少年或儿童的肿瘤,它具有恶性程度高、侵袭性强、疾病进展快等特点,骨肉瘤的病理机制探索和临床治疗是全球面临的一大难题。临床样本和公共临床数据库分析结果表明,伴侣蛋白TRiC的表达量与骨肉瘤的转移和总生存率具有高相关性,TRiC表达量相对较低的患者,其预后生存率更高,复发情况更少。这些数据说明骨肉瘤的进展和预后与TRiC高度相关。TRiC主要存在于真核生物的胞质中,辅助胞内~10 %的蛋白质折叠,是一个由8个亚基组成的大型双环复合物,对细胞内蛋白质的合成、折叠、转运、清除具有重要作用,而肿瘤细胞会“劫持”伴侣蛋白TRiC以维持其高蛋白合成速率下的蛋白稳态。寻找靶向抑制/干扰TRiC的化合物意义重大,但由于TRiC结构巨大,研究工作充满挑战。

中国科学院昆明动物研究所研究员赖仞课题组、挪威奥斯陆大学研究员金杨课题组和华中科技大学研究员盛夏课题组合作,通过虚拟筛选和体外实验验证,发现来自剧毒植物箭毒木(Antiaris toxicaria Lesch.)的天然化合物香豆素β(anticarin-β),能够直接与伴侣蛋白TRiC的关键亚基CCT4相互作用,抑制TRiC活性,并随后抑制STAT3的功能。由于TRiC被化合物干扰,自噬小体和溶酶体的融合被香豆素β阻断,导致OS细胞自噬异常,破坏细胞蛋白稳态进而诱导凋亡。骨肉瘤临床前动物模型揭示了香豆素β在体内同样对骨肉瘤,特别是肺转移型骨肉瘤,具有良好的抑制效果,并且没有明显的系统毒性。这些数据支撑了香豆素β作为CCT4/TRiC抑制剂治疗骨肉瘤的潜力。此外,由于TRiC在维持蛋白质稳态中的重要作用,特异性靶向TRiC的天然化合物香豆素β的发现为TRiC的进一步研究提供了有力的分子工具,对理解TRiC在肿瘤等疾病中的作用具有重要意义。

相关研究成果以Anticarin-β shows a promising anti-osteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis为题,发表在《药学学报》英文刊Acta Pharmaceutica Sinica B上。研究工作得到国家自然科学基金委员会、中科院、云南省科技厅的支持。

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