Bafilomycin induces the p21-mediated growth inhibition of cancer cells under hypoxic conditions by expressing hypoxia-inducible factor-1alpha.

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.

• Authors: Ji-Hong Lim, Jong-Wan Park, Myung-Suk Kim, Sang-Ki Park, Randall S Johnson, Yang-Sook Chun
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 70 Issue 6 Pg. 1856-65 (Dec 2006) ISSN: 0026-895X [Print] United States
• PMID: 16940187 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Hypoxia-Inducible Factor 1, alpha Subunit
• Macrolides
• concanamycin A
• bafilomycin A1

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Cell Hypoxia
• 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)
• Male
• Mice
• Mice, Nude
• Reverse Transcriptase Polymerase Chain Reaction