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[Cancer Research 64, 1475-1482, February 15, 2004]
© 2004 American Association for Cancer Research


Regular Articles

Topoisomerase I-Mediated Inhibition of Hypoxia-Inducible Factor 1

Mechanism and Therapeutic Implications

Annamaria Rapisarda1,2, Badarch Uranchimeg1,2, Olivier Sordet3, Yves Pommier3, Robert H. Shoemaker1 and Giovanni Melillo1,2

1 Developmental Therapeutics Program, 2 Tumor Hypoxia Laboratory, Science Applications International Corporation–Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland, and 3 Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland

We have shown previously that the camptothecin analogue topotecan (TPT), a topoisomerase I (Top 1) poison, inhibits hypoxia-inducible factor 1 (HIF-1) transcriptional activity and HIF-1{alpha} protein accumulation in hypoxia-treated U251 human glioma cells. In this article, we demonstrate that TPT does not affect HIF-1{alpha} protein half-life or mRNA accumulation but inhibits its translation. In addition, we demonstrate that Top 1 is required for the inhibition of HIF-1{alpha} protein accumulation by TPT as shown by experiments performed using camptothecin-resistant cell lines with known Top 1 alterations. Experiments performed with aphidicolin indicated that TPT inhibited HIF-1 protein accumulation in the absence of DNA replication. DNA-damaging agents, such as ionizing radiation and doxorubicin, did not affect HIF-1{alpha} protein accumulation. Ongoing transcription was essential for the inhibition of HIF-1{alpha} protein accumulation by TPT. Our results demonstrate the existence of a novel pathway connecting Top 1-dependent signaling events and the regulation of HIF-1{alpha} protein expression and function. In addition, our findings dissociate the cytotoxic activity of TPT from the inhibition of the HIF-1 pathway and raise the possibility of novel clinical applications of TPT aimed at targeting HIF-1-dependent responses.




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Copyright © 2004 by the American Association for Cancer Research.