Cucurbitacin B-induced G2/M cell cycle arrest of conjunctival melanoma cells mediated by GRP78-FOXM1-KIF20A pathway.
10.1016/j.apsb.2022.05.021
- Author:
Jinlian WEI
1
;
Xin CHEN
1
;
Yongyun LI
2
;
Ruoxi LI
1
;
Keting BAO
1
;
Liang LIAO
1
;
Yuqing XIE
1
;
Tiannuo YANG
1
;
Jin ZHU
1
;
Fei MAO
1
;
Shuaishuai NI
3
;
Renbing JIA
2
;
Xiaofang XU
2
;
Jian LI
1
Author Information
1. State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
2. Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
3. Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
- Publication Type:Journal Article
- Keywords:
Activity-based protein profiling;
Conjunctival melanoma;
Cucurbitacin B;
FOXM1;
G2/M cell cycle;
GRP78;
KIF20A;
Rare tumor
- From:
Acta Pharmaceutica Sinica B
2022;12(10):3861-3876
- CountryChina
- Language:English
-
Abstract:
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 K d 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.
