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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
protein accumulation in hypoxia-treated U251 human glioma cells. In this article, we demonstrate that TPT does not affect HIF-1 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 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 protein accumulation. Ongoing transcription was essential for the inhibition of HIF-1 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 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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