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