Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications.
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-1alpha protein accumulation in hypoxia-treated U251 human glioma cells. In this article, we demonstrate that TPT does not affect HIF-1alpha protein accumulation but inhibits its translation. In addition, we demonstrate that Top 1 is required for the inhibition of HIF-1alpha 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-1alpha protein accumulation in the absence of DNA replication. DNA-damaging agents, such as ionizing radiation and doxorubicin, did not affect HIF-1alpha protein accumulation. Ongoing transcription was essential for the inhibition of HIF-1alpha protein accumulation by TPT. Our results demonstrate the existence of a novel pathway connecting Top 1-dependent signaling events and the regulation of HIF-1alpha 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.
Developmental Therapeutics Program, Tumor Hypoxia Laboratory, Science Applications Corporation-Frederick, Inc., National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Annamaria
A
Rapisarda
Badarch
B
Uranchimeg
Olivier
O
Sordet
Yves
Y
Pommier
Robert H
RH
Shoemaker
Giovanni
G
Melillo
D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000502:physiology; D004249:DNA Damage; D004261:DNA Replication; D004264:DNA Topoisomerases, Type I / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009097:Multienzyme Complexes / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000032:analysis; D058570:TOR Serine-Threonine Kinases; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000494:pharmacology / Q000627:therapeutic use; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D014158:Transcription, Genetic
D003546:Cysteine Endopeptidases; D004264:DNA Topoisomerases, Type I; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009097:Multienzyme Complexes; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D014157:Transcription Factors; C497442:HIF1A protein, human; C546842:MTOR protein, human