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Bafilomycin induces the p21-mediated growth inhibition of cancer cells under hypoxic conditions by expressing hypoxia-inducible factor-1alpha
Cited 53 time in
Web of Science
Cited 57 time in Scopus
- Authors
- Issue Date
- 2006
- Citation
- Mol Pharmacol 70:1856-1865
- Keywords
- Animals ; Antineoplastic Agents/*pharmacology ; Blotting, Western ; Cell Cycle/drug effects ; Cell Division/*drug effects ; Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p21/biosynthesis ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*biosynthesis ; Immunoprecipitation ; In Situ Nick-End Labeling ; Macrolides/*pharmacology ; Mice ; Mice, Nude ; Reverse Transcriptase Polymerase Chain Reaction ; Cell Hypoxia
- Abstract
- Bafilomycin A1, a macrolide antibiotic isolated from Streptomyces species, has been used as an inhibitor of vacuolar H(+) ATPase (V-ATPase). Bafilomycin has been also evaluated as a potential anticancer agent because it inhibits cell proliferation and tumor growth. Although these anticancer effects of bafilomycin are considered to be attributable to the intracellular acidosis by V-ATPase inhibition, the exact mechanism remains unclear. In the present study, we tested the possibility that bafilomycin targets a tumor-promoting factor, hypoxia-inducible factor-1alpha (HIF-1alpha). Bafilomycin A1 and its analog, concanamycin A, were found to up-regulate HIF-1alpha in eight human cancer cell-lines, and this effect is attributed to inhibited degradation of HIF-1alpha protein. Furthermore, the HIF-1alpha induction by bafilomycin was augmented by hypoxia, which caused a robust induction of p21 and cell cycle arrest in cancer cells. The cell cycle inhibition was shown only in cancer cells expressing both HIF-1alpha and p21. In HIF-1alpha(+/+) or HIF-1alpha(-/-) fibrosarcomas grafted in nude mice, bafilomycin showed the HIF-1alpha-dependent anticancer effect. Based on these results, the exorbitant expression of HIF-1alpha is likely to contribute to the anticancer action of bafilomycin.
- ISSN
- 0026-895X (Print)
- Language
- English
- URI
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16940187
https://hdl.handle.net/10371/23141
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