基因敲除
福克斯M1
下调和上调
癌症研究
细胞周期
黑色素瘤
细胞周期检查点
细胞培养
细胞生物学
效应器
化学
细胞
生物
基因
生物化学
遗传学
作者
Jinlian Wei,Xin Chen,Qingfeng Li,Ruoxi Li,Keting Bao,Liang Liao,Yuqing Xie,Tiannuo Yang,Jin Zhu,Fei Mao,Shuaishuai Ni,Renbing Jia,Xiaofang Xu,Jian Li
标识
DOI:10.1016/j.apsb.2022.05.021
摘要
Conjunctival melanoma (CM) is a rare and fatal malignant eye tumor. In this study, we deciphered a novel anti-CM mechanism of a natural tetracyclic compound named as cucurbitacin B (CuB). We found that CuB remarkably inhibited the proliferation of CM cells including CM-AS16, CRMM1, CRMM2 and CM2005.1, without toxicity to normal cells. CuB can also induce CM cells G2/M cell cycle arrest. RNA-seq screening identified KIF20A, a key downstream effector of FOXM1 pathway, was abolished by CuB treatment. Further target identification by activity-based protein profiling chemoproteomic approach revealed that GRP78 is a potential target of CuB. Several lines of evidence demonstrated that CuB interacted with GRP78 and bound with a Kd value of 0.11 μmol/L. Furthermore, ATPase activity evaluation showed that CuB suppressed GRP78 both in human recombinant GRP78 protein and cellular lysates. Knockdown of the GRP78 gene significantly induced the downregulation of FOXM1 and related pathway proteins including KIF20A, underlying an interesting therapeutic perspective. Finally, CuB significantly inhibited tumor progression in NCG mice without causing obvious side effects in vivo. Taken together, our current work proved that GRP78-FOXM1-KIF20A as a promising pathway for CM therapy, and the traditional medicine CuB as a candidate drug to hinder this pathway.
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