Bafilomycin Induces the p21-Mediated Growth Inhibition of Cancer Cells under Hypoxic Conditions by Expressing Hypoxia-Inducible Factor-1{alpha}.
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.[1]References
- Bafilomycin Induces the p21-Mediated Growth Inhibition of Cancer Cells under Hypoxic Conditions by Expressing Hypoxia-Inducible Factor-1{alpha}. Lim, J.H., Park, J.W., Kim, M.S., Park, S.K., Johnson, R.S., Chun, Y.S. Mol. Pharmacol. (2006) [Pubmed]
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