Dihydroartemisinin selectively inhibits PDGFR alpha-positive ovarian cancer growth and metastasis through inducing degradation of PDGFR alpha protein

doi:10.1038/celldisc.2017.42

	Dihydroartemisinin selectively inhibits PDGFR alpha-positive ovarian cancer growth and metastasis through inducing degradation of PDGFR alpha protein
	Li, Xiaoguang 1; Ba, Qian 1; Liu, Yanling 4; Yue, Qingxi 4; Chen, Peizhan 4; Li, Jingquan 1; Zhang, Haibing 4; Ying, Hao 4; Ding, Qiurong 4; Song, Haiyun 1
刊名	CELL DISCOVERY
	2017-11-21
卷号	3
关键词	Dihydroartemisinin Epithelial-mesenchymal transition metastasis ovarian cancer PDGFR alpha
ISSN号	2056-5968
DOI	10.1038/celldisc.2017.42
文献子类	Article
英文摘要	To develop traditional medicines as modern pharmacotherapies, understanding their molecular mechanisms of action can be very helpful. We have recently reported that Artemisinin and its derivatives, which are clinically used anti-malarial drugs, have significant effects against ovarian cancer, but the direct molecular targets and related combination therapy have been unclear. Herein, we report that dihydroartemisinin, one of the most active derivatives of Artemisinin, directly targets platelet-derived growth factor receptor-alpha (PDGFR alpha) to inhibit ovarian cancer cell growth and metastasis. Dihydroartemisinin directly binds to the intercellular domain of PDGFRa, reducing its protein stability by accelerating its ubiquitin-mediated degradation, which further inactivates downstream phosphoinositide 3-Kinase and mitogen-activated protein kinase pathways and subsequently represses epithelial-mesenchymal transition, inhibiting cell growth and metastasis of PDGFR alpha-positive ovarian cancer in vitro and in vivo. A combinational treatment reveals that dihydroartemisinin sensitizes ovarian cancer cells to PDGFR inhibitors. Our clinical study also finds that PDGFRa is overexpressed and positively correlated with high grade and metastasis in human ovarian cancer. Considering that Artemisinin compounds are currently clinically used drugs with favorable safety profiles, the results from this study will potentiate their use in combination with clinically used PDGFRa inhibitors, leading to maximal therapeutic efficacy with minimal adverse effects in PDGFR alpha-positive cancer patients. These findings also shed high light on future development of novel Artemisinin-based targeted therapy.
资助项目	National Nature Science Foundation[81630086] ; National Nature Science Foundation[81427805] ; National Nature Science Foundation[81672763] ; National Nature Science Foundation[31401611] ; National Nature Science Foundation[81502122] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020319] ; Science and Technology Commission of Shanghai Municipality[16391903700] ; Science and Technology Commission of Shanghai Municipality[14391901800] ; [ZDRW-ZS-2017-1]
WOS关键词	EPITHELIAL-MESENCHYMAL TRANSITION ; RECEPTOR TYROSINE KINASES ; CRITICAL ROLES ; ARTEMISININ ; THERAPY ; CELL ; CARCINOMA ; DERIVATIVES ; ARTESUNATE ; TARGET
WOS研究方向	Cell Biology
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000415998600001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272397]
专题	药物化学研究室
通讯作者	Wang, Hui
作者单位	1.Shanghai Jiao Tong Univ, Sch Med, Sch Publ Hlth, Shanghai, Peoples R China; 2.Univ Houston, Coll Pharm, Dept Pharmacol & Pharmaceut Sci, Houston, TX 77030 USA 3.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Food Safety Res, Shanghai, Peoples R China;
推荐引用方式 GB/T 7714	Li, Xiaoguang,Ba, Qian,Liu, Yanling,et al. Dihydroartemisinin selectively inhibits PDGFR alpha-positive ovarian cancer growth and metastasis through inducing degradation of PDGFR alpha protein[J]. CELL DISCOVERY,2017,3.
APA	Li, Xiaoguang.,Ba, Qian.,Liu, Yanling.,Yue, Qingxi.,Chen, Peizhan.,...&Wang, Hui.(2017).Dihydroartemisinin selectively inhibits PDGFR alpha-positive ovarian cancer growth and metastasis through inducing degradation of PDGFR alpha protein.CELL DISCOVERY,3.
MLA	Li, Xiaoguang,et al."Dihydroartemisinin selectively inhibits PDGFR alpha-positive ovarian cancer growth and metastasis through inducing degradation of PDGFR alpha protein".CELL DISCOVERY 3(2017).