A therapeutic target for prostate cancer based on angiogenin-stimulated angiogenesis and cancer cell proliferation

Abstract

Human angiogenin is progressively up-regulated in the prostate epithelial cells during the development of prostate cancer from prostate intraepithelial neoplasia (PIN) to invasive adenocarcinoma. Mouse angiogenin is the most up-regulated gene in AKT-induced PIN in prostate-restricted AKT transgenic mice. These results prompted us to study the role that angiogenin plays in prostate cancer. Here, we report that, in addition to its well established role in mediating angiogenesis, angiogenin also directly stimulates prostate cancer cell proliferation. Angiogenin undergoes nuclear translocation in PC-3 human prostate cancer cells grown both in vitro and in mice. Thus, knocking down angiogenin expression in PC-3 human prostate adenocarcinoma cells inhibits ribosomal RNA transcription, in vitro cell proliferation, colony formation in soft agar, and xenograft growth in athymic mice. Blockade of nuclear translocation of angiogenin by the aminoglycoside antibiotic neomycin inhibited PC-3 cell tumor growth in athymic mice and was accompanied by a decrease in both cancer cell proliferation and angiogenesis. These results suggest that angiogenin has a dual effect, angiogenesis and cancer cell proliferation, in prostate cancer and may serve as a molecular target for drug development. Blocking nuclear translocation of angiogenin could have a combined benefit of antiangiogenesis and chemotherapy in treating prostate cancer.tumor therapy ͉ nuclear translocation ͉ ribosome biogenesis A ngiogenin is a 14-kDa angiogenic ribonuclease originally isolated from HT-29 colon adenocarcinoma cells (1). Its expression is up-regulated in various types of human cancers, including breast (2), cervical (3), colon (4), colorectal (5), endometrial (6), gastric (7), liver (8), kidney (9), ovarian (10), pancreatic (11), prostate (12), and urothelial (13) cancers, as well as astrocytoma (14), leukemia (acute myeloid leukemia and myelodysplastic syndrome) (15, 16), lymphoma (non-Hodgkin's) (17), melanoma (18), osteosarcoma (19), and Wilms' tumor (20). Among them, prostate cancer, in which angiogenin expression is positively correlated with disease progression (12), is of particular interest. Majumder et al. (21) reported that the angiogenin protein content in the serum of patients with hormone refractory prostate cancer (40 patients), in newly diagnosed prostate cancer patients (39 patients), and in control patients with no evidence of prostate cancer (37 patients) was 436 Ϯ 24, 392 Ϯ 17, and 328 Ϯ 20 ng͞ml, respectively. There is a statistically significant difference in serum angiogenin levels between the controls and untreated, hormone-naïve prostate cancer patients (P Ͻ 0.01) and between controls and hormone refractory prostate cancer patients (P Ͻ 0.001). There is also a trend toward higher levels of angiogenin in hormone refractory patients compared with newly diagnosed patients.It is known that circulating angiogenin in normal plasma is mainly produced by the liver (22) and is at a concentration of 250-350 ng͞ml (11, 13). Therefore, if the ...

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.…”

VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting

“…ADM signals angiogenesis by binding calcitonin-receptor-like receptor, which is widely expressed on normal and hypoxic endothelial cells (49,52). Angiogenin was another molecule previously demonstrated to be angiogenic, yet without consequence in TetON-HIF-1:VEGF Δ mice (28,29). In addition to these direct proangiogenic HIF targets, molecules contributing accessory functions such as matrix degradation and its modulation, MMP9, MMP3, and PAI-1, and vascular dilatation, iNOS, were also up-regulated in TetON-HIF-1:VEGF Δ mice.…”

“…Previous work has highlighted the angiogenic potential of several direct and indirect HIF-1 transcriptional targets (23)(24)(25)(26)(27)(28)(29). To determine whether these targets were induced by HIF-1 in the absence of VEGF, whole skin extracts were analyzed by using RT-PCR, ELISA, or antibody microarrays (Fig.…”

A New Terrein Glucoside, a Novel Inhibitor of Angiogenin Secretion in Tumor Angiogenesis

“…It is known that angiogenin is secreted from human cancer cells and human normal cells [10]. Endogenous angiogenin in endothelial cells is related to cell proliferation and angiogenesis [22].…”