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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 55 time in Scopus
Authors
Lim, Ji-Hong; Park, Jong-Wan; Kim, Myung-Suk; Park, Sang-Ki; Johnson, Randall S.; Chun, Yang-Sook
Issue Date
2006
Publisher
American Society for Pharmacology and Experimental Therapeutics (ASPET)
Citation
Mol Pharmacol 70:1856-1865
Keywords
AnimalsAntineoplastic Agents/*pharmacologyBlotting, WesternCell Cycle/drug effectsCell Division/*drug effects*Cell HypoxiaCell Line, TumorCyclin-Dependent Kinase Inhibitor p21/biosynthesisHumansHypoxia-Inducible Factor 1, alpha Subunit/*biosynthesisImmunoprecipitationIn Situ Nick-End LabelingMacrolides/*pharmacologyMiceMice, NudeReverse Transcriptase Polymerase Chain Reaction
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
DOI
https://doi.org/10.1124/mol.106.028076
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College of Medicine/School of Medicine (의과대학/대학원)Pharmacology (약리학전공)Journal Papers (저널논문_약리학전공)
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