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

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-1a (HIF-1a) activity in human cancer cells. In particular, we provide evidence that low concentrations of camptothecin, without interfering with HIF-1a mRNA levels, can reduce HIF-1a protein expression and activity. As luciferase assays demonstrated the involvement of the HIF-1a mRNA 3 0 untranslated region in camptothecin-induced impairment of HIF-1aprotein regulation, we performed microarray analysis to identify camptothecin-induced modification of microRNAs (miRNA) targeting HIF-1a mRNA under hypoxic-mimetic conditions. The selected miRNAs were then further analyzed, demonstrating a role for miR-17-5p and miR-155 in HIF-1a protein expression after camptothecin treatments. The present findings establish miRNAs as key factors in a molecular pathway connecting Top1 inhibition and human HIF-1a protein regulation and activity, widening the biologic and molecular activity of camptothecin derivatives and the perspective for novel clinical interventions. Mol Cancer Ther; 13(1); 239-48. Ó2013 AACR.

MicroRNA-18a regulates invasive meningiomas via hypoxia-inducible factor-1α

“…However, the activity and regulatory mechanisms of miR-18a are not fixed across various pathological and physiological conditions, or in different types of tumors, and factors that are associated with invasive meningiomas are not limited to HIF-1α (23)(24)(25). In addition, there are abundant miRNAs that may potentially regulate these factors.…”

A map describing the association between effective components of traditional Chinese medicine and signaling pathways in cancer cells in vitro and in vivo

“…It also can induce p53-dependent DNA damage in renal cell carcinoma (8). In another report, camptothecin induces apoptosis through the hypoxia-inducible factor-1α (HIF-1α) pathway in HeLa (human cervix adenocarcinoma cell line) (9). In the HCT116 coloretctal cancer cell, camptothecin can induce apoptosis through the AMPK-TSC2-mTOR pathway (10).…”

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“…Mechanistically it was reported that camptothecin exerted its inhibitory effects via upregulating expression of miR-155 (Bertozzi et al, 2014).…”