文献类型：期刊文献

英文题名：Cucurbitacin B-induced G2/M cell cycle arrest of conjunctival melanoma cells mediated by GRP78-FOXM1-KIF20A pathway

作者：Wei, Jinlian[1];Chen, Xin[1];Li, Yongyun[2];Li, Ruoxi[1];Bao, Keting[1];Liao, Liang[1];Xie, Yuqing[1];Yang, Tiannuo[1];Zhu, Jin[1];Mao, Fei[1];Ni, Shuaishuai[3];Jia, Renbing[2];Xu, Xiaofang[2];Li, Jian[1,4,5,6]

机构：[1]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Frontiers Sci Ctr Materiobiol & Dynam Chem, Sch Pharm, Shanghai 200237, Peoples R China;[2]Shanghai Jiao Tong Univ, Peoples Hosp 9, Sch Med, Dept Ophthalmol, Shanghai 200025, Peoples R China;[3]Shanghai Univ Tradit Chinese Med, Longhua Hosp, Canc Inst, Shanghai 200032, Peoples R China;[4]Dali Univ, Coll Pharm, Yunnan Key Lab Screening & Res Antipathogen Plant, Dali 671000, Peoples R China;[5]Tongji Univ, Shanghai Peoples Hosp 10, Clin Med Sci & Tech Innovat Ctr, Sch Med, Shanghai 200092, Peoples R China;[6]Hainan Univ, Coll Pharm, Key Lab Trop Biol Resources, Minist Educ, Haikou 570228, Peoples R China

年份：2022

卷号：12

期号：10

起止页码：3861

外文期刊名：ACTA PHARMACEUTICA SINICA B

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000870351800005)】；

基金：This work was supported by the National Mega-project for Innovative Drugs of China (2019ZX09721001-004-003) , the Na-tional Natural Science Foundation of China (82003603 and 81872747) , the Innovative Research Team of High-level Local Universities in Shanghai, the National Special Fund for State Key Laboratory of Bioreactor Engineering (2060204, China) , Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (2021 Sci & Tech 03-28, China) .

语种：英文

外文关键词：Conjunctival melanoma; Cucurbitacin B; Activity-based protein profiling; G2; M cell cycle; GRP78; FOXM1; KIF20A; Rare tumor

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 mmol/L. Furthermore, ATPase activity evaluation showed that CuB suppressed GRP78 both in hu-man 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.(c) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).