Neamine Inhibits Prostate Cancer Growth by Suppressing Angiogenin-Mediated rRNA Transcription

Abstract

Purpose: Angiogenin (ANG) undergoes nuclear translocation and stimulates rRNA transcription in both prostate cancer cells and endothelial cells. The purpose of this study is to assess the antitumor activity of neamine, a nontoxic degradation product of neomycin that blocks nuclear translocation of ANG. Experimental Design: The anti-prostate cancer activity of neamine was first evaluated in a xenograft animal model. It was then examined in the murine prostate-restricted AKT transgenic mice that develop prostate intraepithelial neoplasia (PIN) owing to AKT transgene overexpression. Results: Neamine inhibits xenograft growth of PC-3 human prostate cancer cells in athymic mice. It blocks nuclear translocation of ANG and inhibits rRNA transcription, cell proliferation, and angiogenesis. Neamine also prevents AKT-induced PIN formation as well as reverses fully developed PIN in murine prostate-restricted AKT mice, accompanied by a decrease in rRNA synthesis, cell proliferation, and angiogenesis and an increase in prostate epithelial cell apoptosis. Conclusion: We confirmed that ANG is a molecular target for cancer drug development and that blocking nuclear translocation of ANG is an effective means to inhibit its activity. Our results also suggested that neamine is a lead compound for further preclinical evaluation.

Transcription of Angiogenin and Ribonuclease 4 Is Regulated by RNA Polymerase III Elements and a CCCTC Binding Factor (CTCF)-dependent Intragenic Chromatin Loop

“…Among these, 6 belong to the nuclear receptor superfamily (Table 1). Preferential enrichment of the nuclear receptor class of TFs on ANG and RNASE4 promoter is consistent with known functions of ANG in hormone-regulated prostate (5,(33)(34)(35) and breast (36,37) cancer.…”

An electrochemical functional assay for the sensing of nitric oxide release induced by angiogenic factors

“…Therefore, we cannot yet reach a conclusion on the role of nuclear translocation in ANG induced NO release. Neamine, a less toxic antibiotic produced by methanolysis of neomycin, shows the same antiangiogenic effects and also blocks ANG nuclear translocation (40), but does not block the phosphorylation of Akt (56). This molecule could therefore be a good candidate for selective inhibition of ANG nuclear translocation.…”

Angiogenin is upregulated during the alloreactive immune response and has no effect on the T-cell expansion phase, whereas it affects the contraction phase by inhibiting CD4+ T-cell apoptosis

“…For this purpose, the two-way MLR was used as a measure of alloreactivity (15), along with neamine (an angiogenin nuclear translocation inhibitor) treatment (2,(16)(17)(18). At 100 µM neamine did not induce cell necrosis in resting PBMCs or MLRs.…”

“…Although suppression of cell proliferation by neamine is typical in various cancer cell lines tested (1,2,(16)(17)(18), this effect is not universal. For instance, neamine inhibits nuclear translocation of angiogenin in both HSC-2 and SAS cells, but proliferation is only suppressed in HSC-2 cells lines (17).…”

“…Neamine is a neomycin derivative with low toxicity, which represses rRNA transcription and cell proliferation through inhibiting angiogenin nuclear translocation (2,(16)(17)(18). In addition, nuclear translocation of angiogenin may be required for its ribonuclease activity.…”