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Bafilomycin Induces the p21-Mediated Growth Inhibition of Cancer Cells under Hypoxic Conditions by Expressing Hypoxia-Inducible Factor-1

Cancer Research Institute (J.-H.L., Y.-S.C.), Department of Physiology (Y.-S.C.), and Department of Pharmacology (J.-W.P., M.-S.K.), Seoul National University College of Medicine, Seoul, Korea; and Molecular Biology Section, Division of Biological Sciences, University of California San Diego, La Jolla, California (S.-K.P., R.S.J.)

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-1 (HIF-1). Bafilomycin A1 and its analog, concanamycin A, were found to up-regulate HIF-1 in eight human cancer cell-lines, and this effect is attributed to inhibited degradation of HIF-1 protein. Furthermore, the HIF-1 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-1 and p21. In HIF-1(+/+) or HIF-1(-/-) fibrosarcomas grafted in nude mice, bafilomycin showed the HIF-1-dependent anticancer effect. Based on these results, the exorbitant expression of HIF-1 is likely to contribute to the anticancer action of bafilomycin.

Received for publication June 19, 2006.

Accepted for publication August 25, 2006.

Address correspondence to: Dr. Y. S. Chun, Department of Physiology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea. E-mail: chunys{at}snu.ac.kr

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