The Natural Inhibitor of DNA Topoisomerase I, Camptothecin, Modulates HIF-1 alpha Activity by Changing miR Expression Patterns in Human Cancer Cells

摘要

DNA topoisomerase I (Top1) inhibition by camptothecin derivatives can impair the hypoxia-induced cell transcriptional response. In the present work, we determined molecular aspects of the mechanism of camptothecin's effects on hypoxia-inducible factor-1 alpha (HIF-1 alpha) activity in human cancer cells. In particular, we provide evidence that low concentrations of camptothecin, without interfering with HIF-1 alpha mRNA levels, can reduce HIF-1 alpha protein expression and activity. As luciferase assays demonstrated the involvement of the HIF-1 alpha mRNA 3' untranslated region in camptothecin-induced impairment of HIF-1 alpha protein regulation, we performed microarray analysis to identify camptothecin-induced modification of microRNAs (miRNA) targeting HIF-1 alpha mRNA under hypoxic-mimetic conditions. The selected miRNAs were then further analyzed, demonstrating a role for miR-17-5p and miR-155 in HIF-1 alpha protein expression after camptothecin treatments. The present findings establish miRNAs as key factors in a molecular pathway connecting Top1 inhibition and human HIF-1 alpha protein regulation and activity, widening the biologic and molecular activity of camptothecin derivatives and the perspective for novel clinical interventions. (C)2013 AACR.