Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44

doi:10.1158/1535-7163.MCT-15-0753

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	Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44
	Yi, Jun-Mei 1; Huan, Xia-Juan 1; Song, Shan-Shan 1; Zhou, Hu2 ; Wang, Ying-Qing1 ; Miao, Ze-Hong 1
刊名	MOLECULAR CANCER THERAPEUTICS
	2016-07
卷号	15 期号:7 页码:1495-1503
ISSN号	1535-7163
DOI	10.1158/1535-7163.MCT-15-0753
文献子类	Article
英文摘要	Multidrug resistance (MDR) is a major cause of tumor treatment failure; therefore, drugs that can avoid this outcome are urgently needed. We studied triptolide, which directly kills MDR tumor cells with a high potency and a broad spectrum of cell death. Triptolide did not inhibit P-glycoprotein (P-gp) drug efflux and reduced P-gp and MDR1 mRNA resulting from transcription inhibition. Transcription factors including c-MYC, SOX-2, OCT-4, and NANOG were not correlated with triptolide-induced cell killing, but RPB1, the largest subunit of RNA polymerase II, was critical in mediating triptolide's inhibition of MDR cells. Triptolide elicited antitumor and anti-MDR activity through a universal mechanism: by activating CDK7 by phosphorylating Thr170 in both parental and MDR cell lines and in SK-OV-3 cells. The CDK7-selective inhibitor BS-181 partially rescued cell killing induced by 72-hour treatment of triptolide, which may be due to partial rescue of RPB1 degradation. We suggest that a precise phosphorylation site on RPB1 (Ser1878) was phosphorylated by CDK7 in response to triptolide. In addition, XPB and p44, two transcription factor TFIIH subunits, did not contribute to tripto-lide-driven RPB1 degradation and cell killing, although XPB was reported to covalently bind to triptolide. Several clinical trials are underway to test triptolide and its analogues for treating cancer and other diseases, so our data may help expand potential clinical uses of triptolide, as well as offer a compound that overcomes tumor MDR. Future investigations into the primary molecular target(s) of triptolide responsible for RPB1 degradation may suggest novel anti-MDR target(s) for therapeutic development. (C) 2016 AACR.
资助项目	National Basic Research Program of China[2012CB932502] ; National Natural Science Foundation of China[81321092] ; State Key Laboratory of Drug Research[00000000]
WOS关键词	NATURAL-PRODUCT TRIPTOLIDE ; RNA-POLYMERASE-II ; STEM-CELLS ; APOPTOSIS INDUCTION ; TOPOISOMERASE-II ; CANCER ; ACTIVATION ; MECHANISMS ; INHIBITOR ; SUBUNIT
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000381087200007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275966]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Wang, Ying-Qing; Miao, Ze-Hong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Yi, Jun-Mei,Huan, Xia-Juan,Song, Shan-Shan,et al. Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44[J]. MOLECULAR CANCER THERAPEUTICS,2016,15(7):1495-1503.
APA	Yi, Jun-Mei,Huan, Xia-Juan,Song, Shan-Shan,Zhou, Hu,Wang, Ying-Qing,&Miao, Ze-Hong.(2016).Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44.MOLECULAR CANCER THERAPEUTICS,15(7),1495-1503.
MLA	Yi, Jun-Mei,et al."Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44".MOLECULAR CANCER THERAPEUTICS 15.7(2016):1495-1503.