Inhibitory action of Celastrol on hypoxia-mediated angiogenesis and metastasis via the HIF-1α pathway.
Celastrol, a natural biologically active compound isolated from Tripterygium wilfordii Hook F root extracts, has been shown to possess antitumor properties and therefore, is an interesting candidate for the development of novel chemotherapeutic cancer agents. In this study, we have demonstrated that Celastrol is a potent inhibitor of hypoxia-induced angiogenic and metastatic activity as shown by a decrease in the proliferation of both endothelial and cancer cells, blocking of migration as well as of tube formation of endothelial cells, and by inhibition of cancer cell invasion under hypoxic conditions. Moreover, Celastrol decreased hypoxia-inducible factor-1α (HIF-1α) mRNA levels under both normoxia and hypoxia and inhibited hypoxia-induced accumulation of nuclear HIF-1α protein. Meanwhile, inhibition of nuclear HIF-1α protein levels were accompanied by a reduction in the transcriptional activity of HIF-1α target genes, including VEGF. In addition, the inhibitory effect of Celastrol on HIF-1α protein was partly due to its suppression of HSP90 activity. We conclude that Celastrol regulates HIF-1α at multiple levels that may together or individually contribute to its antitumor activity against hypoxia-induced angiogenesis and metastasis.
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
Lili
L
Huang
Zefu
Z
Zhang
Sheng
S
Zhang
Jinghua
J
Ren
Ruiguang
R
Zhang
Hui
H
Zeng
Qingfeng
Q
Li
Gang
G
Wu
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053978:Pentacyclic Triterpenes; D018517:Plant Roots / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D029757:Tripterygium / Q000737:chemistry; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D053978:Pentacyclic Triterpenes; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014315:Triterpenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C050414:celastrol