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Both Microtubule-Stabilizing and Microtubule-Destabilizing Drugs Inhibit Hypoxia-Inducible Factor-1 Accumulation and Activity by Disrupting Microtubule Function

¹ Department of Hematology and Oncology, Winship Cancer Institute, Robert Woodruff Health Sciences Center, Emory University School of Medicine, Atlanta, Georgia and ² Medical Oncology Center, Hospital Universitari Germans Trias i Pujol, Institut Català d'Oncologia, Badalona, Barcelona, Spain

Requests for reprints: Paraskevi Giannakakou, Winship Cancer Institute, Emory University School of Medicine, 1365-B Clifton Road, NE-Suite B4100, Atlanta, GA 30322. Phone: 404-778-7729; Fax: 404-778-3965; E-mail: paraskevi_giannakakou{at}emory.org

We have recently identified a mechanistic link between disruption of the microtubule cytoskeleton and inhibition of tumor angiogenesis via the hypoxia-inducible factor-1 (HIF-1) pathway. Based on this model, we hypothesized that other microtubule-targeting drugs may have a similar effect on HIF-1. To test that hypothesis, we studied the effects of different clinically relevant microtubule-disrupting agents, including taxotere, epothilone B, discodermolide, vincristine, 2-methoxyestradiol, and colchicine. In all cases, HIF-1 protein, but not mRNA, was down-regulated in a drug dose–dependent manner. In addition, HIF-1 transcriptional activity was also inhibited by all drugs tested. To further examine whether these effects were dependent on microtubule network disruption, we tested the ability of epothilone B to inhibit HIF-1 protein in the human ovarian cancer cell line 1A9 and its ß-tubulin mutant epothilone-resistant subclone 1A9/A8. Our data showed that epothilone B treatment down-regulated HIF-1 protein in the parental 1A9 cells but had no effect in the resistant 1A9/A8 cells. These observations were confirmed by confocal microscopy, which showed impaired nuclear accumulation of HIF-1 in parental 1A9 cells at epothilone B concentrations that induced extensive microtubule stabilization. In contrast, epothilone B treatment had no effect on either microtubules or HIF-1 nuclear accumulation in the resistant 1A9/A8 cells. Furthermore, epothilone B inhibited HIF-1 transcriptional activity in 1A9 cells, as evidenced by a hypoxia response element-luciferase reporter assay, but had no effect on HIF-1 activity in the resistant 1A9/A8 cells. These data directly link ß-tubulin drug binding with HIF-1 protein inhibition. Our results further provide a strong rationale for testing taxanes and epothilones in clinical trials targeting HIF-1 in cancer patients.

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