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First published on August 28, 2006; DOI: 10.1124/mol.106.028076

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Received for publication June 21, 2006.
Revised August 24, 2006.
Accepted for publication August 25, 2006.

Bafilomycin induces the p21-mediated growth inhibition of cancer cells under hypoxic conditions by expressing HIF-1{alpha}

Ji-Hong Lim 1, Jong-Wan Park 1, Myung-Suk Kim 1, Sang-Ki Park 2, Randall S Johnson 2, Yang-Sook Chun 1*

1 Seoul National University College of Medicine 2 University of California San Diego

* Address correspondence to: E-mail: chunys{at}snu.ac.kr

Abstract

Bafilomycin A1, a macrolide antibiotic isolated from Streptomyces sp, has been used as an inhibitor of vacuolar H+ ATPase. Bafilomycin has been also evaluated as a potential anticancer agent since 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-1{alpha} (HIF-1{alpha}). Bafilomycin A1 and its analogue, concanamycin A, were found to up-regulate HIF-1{alpha} in 8 human cancer cell-lines, and this effect is attributed to inhibited degradation of HIF-1{alpha} protein. Furthermore, the HIF-1{alpha} expression by bafilomycin was exaggerated 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-1{alpha} and p21. In HIF-1{alpha}(+/+) or HIF-1{alpha}(-/-) fibrosarcomas grafted in nude mice, bafilomycin showed the HIF-1{alpha}-dependent anticancer effect. Based on these results, the exorbitant expression of HIF-1{alpha} is likely to contribute to the anticancer action of bafilomycin.


Key words: Mechanisms of cell killing/apoptosis, Angiogenesis


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