S-Space College of Medicine/School of Medicine (의과대학/대학원) Pharmacology (약리학전공) Journal Papers (저널논문_약리학전공)
Bafilomycin induces the p21-mediated growth inhibition of cancer cells under hypoxic conditions by expressing hypoxia-inducible factor-1alpha
- Lim, Ji-Hong; Park, Jong-Wan; Kim, Myung-Suk; Park, Sang-Ki; Johnson, Randall S.; Chun, Yang-Sook
- Issue Date
- Mol Pharmacol 70:1856-1865
- 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; Mice; Mice, Nude; Reverse Transcriptase Polymerase Chain Reaction
- 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.
- 0026-895X (Print)
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