期刊
MOLECULAR CANCER THERAPEUTICS
卷 7, 期 1, 页码 90-100出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-07-0463
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- NCI NIH HHS [CA90821, CA109552, CA077204] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA077204, P01CA109552, U54CA090821] Funding Source: NIH RePORTER
We have reported previously that PX-478 (S-2-amino-3-[4'-N,N,-bis(chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) has potent antitumor activity against a variety of human tumor xenografts associated with the levels of the hypoxia-inducible factor-1 alpha (HIF-1 alpha) within the tumor. We now report that PX-478 inhibits HIF-1 alpha protein levels and transactivation in a variety of cancer cell lines. Hypoxia-induced vascular endothelial growth factor formation was inhibited by PX-478, whereas baseline levels of vascular endothelial growth factor in normoxia were unaffected. Studies of the mechanism of PX-478 action showed that HIF-1 alpha inhibition occurs in both normoxia and hypoxia and does not require pVHL or p53. In addition, PX-478 decreases levels of HIF-1 alpha mRNA and inhibits translation as determined by S-35 labeling experiments and reporter assays using the 5' untranslated region of HIF-1 alpha. Moreover, to a lesser extent, PX-478 also inhibits HIF-1 alpha deubiquitination resulting in increased levels of polyubiquitinated HIF-1 alpha. The inhibitory effect of PX-478 on HIF-1 alpha levels is primarily due to its inhibition of translation because HIF-1 alpha translation continues in hypoxia when translation of most proteins is decreased. We conclude that PX-478 inhibits HIF-1 alpha at multiple levels that together or individually may contribute to its antitumor activity against HIF-1 alpha-expressing tumors.
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