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 ...

CCN2 was critically involved in osteolytic metastasis and was induced by PKA- and PKC-dependent activation of ERK1/2 signaling by PTHrP. Thus, CCN2 may be a new molecular target for anti-osteolytic therapy to shut off the PTHrP-CCN2 signaling pathway.

RFA is more useful than PMCT for the treatment of small HCC because it is minimally invasive and achieves a low local recurrence rate, high survival rate, and extensive necrosis after only a few treatment sessions.

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.

Angiogenin (ANG), originally identified as an angiogenic ribonuclease, has recently been shown to play a direct role in prostate cancer cell proliferation by mediating ribosomal RNA (rRNA) transcription. ANG is upregulated in human prostate cancer and is the most significantly upregulated gene in AKT-driven prostate intraepithelial neoplasia (PIN) in mice. Enhanced cell proliferation in the PIN lesions requires increased ribosome biogenesis, a multistep process involving an orchestrated production of ribosomal proteins and rRNA. AKT is known to enhance ribosomal protein production through the mammalian target of rapamycin (mTOR) pathway. However, it was unknown how rRNA is proportionally increased. Here, we report that ANG is essential for AKT-driven PIN formation and survival. We showed that upregulation of ANG in the AKT over-expressing mouse prostates is an early and lasting event. It occurs before PIN initiation and lasts beyond PIN is fully developed. Knocking-down ANG expression by intraprostate injection of lentivirus-mediated ANG-specific siRNA prevents AKT-induced PIN formation without affecting AKT expression and its signaling through the mTOR pathway. Neomycin, an aminoglycoside that blocks nuclear translocation of ANG, and N65828, a small-molecule enzymatic inhibitor of the ribonucleolytic activity of ANG, both prevent AKT-induced PIN formation and reverse established PIN. They also decrease nucleolar organizer region (NOR), restore cell size, and normalize luminal architectures of the prostate despite continuous activation of AKT. All three types of the ANG inhibitor suppress rRNA transcription of the prostate luminal epithelial cells and inhibit AKT-induced PIN indicating an essential role of ANG in AKT-mediated cell proliferation and survival.