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

The Natural Inhibitor of DNA Topoisomerase I, Camptothecin, Modulates HIF-1 alpha Activity by Changing miR Expression Patterns in Human Cancer Cells / D. Bertozzi;J. Marinello;S. G. Manzo;F. Fornari;L. Gramantieri;G. Capranico. - In: MOLECULAR CANCER THERAPEUTICS. - ISSN 1535-7163. - STAMPA. - 13:(2014), pp. 239-248. [10.1158/1535-7163.MCT-13-0729]

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

BERTOZZI, DAVIDE;MARINELLO, JESSICA;MANZO, STEFANO GIUSTINO;F. Fornari;CAPRANICO, GIOVANNI
2014

Abstract

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-1α (HIF-1α) activity in human cancer cells. In particular, we provide evidence that low concentrations of camptothecin, without interfering with HIF-1α mRNA levels, can reduce HIF-1α protein expression and activity. As luciferase assays demonstrated the involvement of the HIF-1α mRNA 3' untranslated region in camptothecin-induced impairment of HIF-1α protein regulation, we performed microarray analysis to identify camptothecin-induced modification of microRNAs (miRNA) targeting HIF-1α mRNA under hypoxic-mimetic conditions. The selected miRNAs were then further analyzed, demonstrating a role for miR-17-5p and miR-155 in HIF-1α protein expression after camptothecin treatments. The present findings establish miRNAs as key factors in a molecular pathway connecting Top1 inhibition and human HIF-1α protein regulation and activity, widening the biologic and molecular activity of camptothecin derivatives and the perspective for novel clinical interventions.
2014
The Natural Inhibitor of DNA Topoisomerase I, Camptothecin, Modulates HIF-1 alpha Activity by Changing miR Expression Patterns in Human Cancer Cells / D. Bertozzi;J. Marinello;S. G. Manzo;F. Fornari;L. Gramantieri;G. Capranico. - In: MOLECULAR CANCER THERAPEUTICS. - ISSN 1535-7163. - STAMPA. - 13:(2014), pp. 239-248. [10.1158/1535-7163.MCT-13-0729]
D. Bertozzi;J. Marinello;S. G. Manzo;F. Fornari;L. Gramantieri;G. Capranico
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/278326
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