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.

The natural inhibitor of DNA topoisomerase I, camptothecin, modulates HIF-1α 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. - 13:1(2014 Jan), pp. 239-248. [10.1158/1535-7163.MCT-13-0729]

The natural inhibitor of DNA topoisomerase I, camptothecin, modulates HIF-1α activity by changing miR expression patterns in human cancer cells

S.G. Manzo;F. Fornari;
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-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.
Settore BIO/11 - Biologia Molecolare
gen-2014
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/956579
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