%0 Journal Article
%T Increased accumulation of hypoxia-inducible factor-1¦Á with reduced transcriptional activity mediates the antitumor effect of triptolide
%A Zhao-Li Zhou
%A Zhi-Guo Luo
%A Bing Yu
%A Yi Jiang
%A Yi Chen
%A Jian-Ming Feng
%A Mei Dai
%A Lin-Jiang Tong
%A Zheng Li
%A Yuan-Chao Li
%A Jian Ding
%A Ze-Hong Miao
%J Molecular Cancer
%D 2010
%I BioMed Central
%R 10.1186/1476-4598-9-268
%X Triptolide was observed to inhibit the proliferation of SKOV-3 cells, and meanwhile, to enhance the accumulation of HIF-1¦Á protein in SKOV-3, A549 and DU145 cells under different conditions. Triptolide did not change the kinetics or nuclear localization of HIF-1¦Á protein or the 26 S proteasome activity in SKOV-3 cells. However, triptolide was found to increase the levels of HIF-1¦Á mRNA. Unexpectedly, the HIF-1¦Á 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¦Á partially prevented the cytotoxicity and apoptosis triggered by triptolide.The potent induction of HIF-1¦Á 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¦Á functions in an unresolved nature or condition.Hypoxia-inducible factor-1¦Á (HIF-1¦Á) is a critical transcription factor responsible for adaptive responses of cancer cells to reduced O2 availability [1]. Through modulation of the expression of at least 70 genes, HIF-1¦Á is extensively involved in tumor survival, aggressive progression, drug resistance and angiogenesis [2]. Elevated levels of HIF-1¦Á protein are observed in various human primary and metastatic cancers, either as direct results of intratumoral hypoxia or secondary to genetic alterations in oncogenes or tumor suppressor genes [3,4]. Those cancers are generally relatively poorly responsive to chemotherapy or radiotherapy with poor prognosis [5]. Thus, HIF-1¦Á has been proposed as a promising anticancer target [6]. On the other ha
%U http://www.molecular-cancer.com/content/9/1/268