Increased accumulation of hypoxia-inducible factor-1 alpha with reduced transcriptional activity mediates the antitumor effect of triptolide

doi:10.1186/1476-4598-9-268

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Increased accumulation of hypoxia-inducible factor-1 alpha with reduced transcriptional activity mediates the antitumor effect of triptolide
	Zhou, Zhao-Li 1,4; Luo, Zhi-Guo 3; Yu, Bing 1; Jiang, Yi1 ; Chen, Yi1 ; Feng, Jian-Ming 1; Dai, Mei 1; Tong, Lin-Jiang 1; Li, Zheng 2; Li, Yuan-Chao 2
刊名	MOLECULAR CANCER
	2010-10-11
卷号	9
ISSN号	1476-4598
DOI	10.1186/1476-4598-9-268
文献子类	Article
英文摘要	Background: Hypoxia-inducible factor-1 alpha (HIF-1 alpha), a critical transcription factor to reduced O-2 availability, has been demonstrated to be extensively involved in tumor survival, aggressive progression, drug resistance and angiogenesis. Thus it has been considered as a potential anticancer target. Triptolide is the main principle responsible for the biological activities of the Traditional Chinese Medicine tripterygium wilfordii Hook F. Triptolide possesses great chemotherapy potential for cancer with its broad-spectrum anticancer, antiangiogenesis, and drug-resistance circumvention activities. Numerous biological molecules inhibited by triptolide have been viewed as its possible targets. However, the anticancer action mechanisms of triptolide remains to be further investigated. Here we used human ovarian SKOV-3 cancer cells as a model to probe the effect of triptolide on HIF-1 alpha. Results: Triptolide was observed to inhibit the proliferation of SKOV-3 cells, and meanwhile, to enhance the accumulation of HIF-1 alpha protein in SKOV-3, A549 and DU145 cells under different conditions. Triptolide did not change the kinetics or nuclear localization of HIF-1 alpha protein or the 26 S proteasome activity in SKOV-3 cells. However, triptolide was found to increase the levels of HIF-1 alpha mRNA. Unexpectedly, the HIF-1a protein induced by triptolide appeared to lose its transcriptional activity, as evidenced by the decreased mRNA levels of its target genes including VEGF, BNIP3 and CAIX. The results were further strengthened by the lowered secretion of VEGF protein, the reduced sprout outgrowth from the rat aorta rings and the inhibitory expression of the hypoxia responsive element-driven luciferase reporter gene. Moreover, the silencing of HIF-1 alpha partially prevented the cytotoxicity and apoptosis triggered by triptolide. Conclusions: The potent induction of HIF-1 alpha protein involved in its cytotoxicity, together with the suppression of HIF-1 transcriptional activity, indicates the great therapeutic potential of triptolide as an anticancer drug. Meanwhile, our data further stress the possibility that HIF-1 alpha functions in an unresolved nature or condition.
资助项目	National Natural Science Foundation of China (NSFC)[30721005] ; National Natural Science Foundation of China (NSFC)[81025020] ; National Science & Technology of China[2009ZX09301-001] ; State Key Laboratory of Drug Research[SIMM0912QN-02] ; National Basic Research Program of China[2010CB934000]
WOS关键词	MYELOGENOUS LEUKEMIA-CELLS ; KAPPA-B ACTIVATION ; CANCER-CELLS ; FACTOR (HIF)-1-ALPHA ; TUMOR ANGIOGENESIS ; APOPTOSIS ; EXPRESSION ; HIF-1-ALPHA ; DEGRADATION ; PATHWAY
WOS研究方向	Biochemistry & Molecular Biology ; Oncology
语种	英语
出版者	BIOMED CENTRAL LTD
WOS记录号	WOS:000283261600001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278747]
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	Miao, Ze-Hong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, Shanghai 201203, Peoples R China; 3.Fudan Univ, Shanghai Med Sch, Canc Hosp, Dept Med Oncol, Shanghai 200032, Peoples R China; 4.Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Zhao-Li,Luo, Zhi-Guo,Yu, Bing,et al. Increased accumulation of hypoxia-inducible factor-1 alpha with reduced transcriptional activity mediates the antitumor effect of triptolide[J]. MOLECULAR CANCER,2010,9.
APA	Zhou, Zhao-Li.,Luo, Zhi-Guo.,Yu, Bing.,Jiang, Yi.,Chen, Yi.,...&Miao, Ze-Hong.(2010).Increased accumulation of hypoxia-inducible factor-1 alpha with reduced transcriptional activity mediates the antitumor effect of triptolide.MOLECULAR CANCER,9.
MLA	Zhou, Zhao-Li,et al."Increased accumulation of hypoxia-inducible factor-1 alpha with reduced transcriptional activity mediates the antitumor effect of triptolide".MOLECULAR CANCER 9(2010).