Significance of chemoprevention for prostate cancer development: experimental in vivo approaches to chemoprevention.
ABSTRACT Prostate cancer is the most common tumor in men in Western countries and mortality in Asian countries from the disease appears to be constantly increasing. Characteristics include (i) frequent discovery of latent carcinoma, even in countries with low incidences of clinical cancer; (ii) very long time to clinically significant cancer; (iii) few patients under 50 years of age (primarily a disease of elderly men); (iv) strong influences of environmental factors such as food; (v) temporal effectiveness of androgen deprival therapy; and (vi) no effective therapeutic approaches once hormone-refractory neoplasms have developed. Therefore prostate cancer is particularly indicated for preventive efforts, especially chemoprevention. Several large-scale chemoprevention trials have in fact been conducted and some have found suppressive effects. However, not all have been proven to have benefit. Experimental preclinical investigations, particularly using animal models, are recommended to find better chemopreventive agents with less adverse effects. Data using rat models have generated very interesting findings from which mechanism-based strategies can be proposed. In the present report the importance of chemoprevention of prostate cancer will be discussed using the data on human and rat prostate cancer development.
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ABSTRACT: Histone H1, one of the histone superfamilies, is known to determine chromatin structure and alter gene expression. It also contributes to regulation of cell proliferation in breast cancer. We hypothesized a similar association in prostate cancer, and therefore examined relationships between histone H1 expression and Gleason pattern, Ki-67 and androgen receptor levels in a series of prostate cancer tissues and cell lines. Histone H1 positive cancer cells increased with the Gleason pattern. Gleason pattern 3 tumors were divided into two groups, one with high histone H1 positivity (H1-high cases, 60-100% positivity) and the other with low histone H1 positivity (H1-low cases, 0-20% positivity). Ki-67 or androgen receptor positivity in H1-high cases was significantly higher than in H1-low cases. PC3 cells demonstrated more frequent histone H1 and Ki-67 positivity as compared to LNCaP cells. Silencing of histone H1 by siRNA transfection significantly reduced cell proliferation in LNCaP and PC3. These findings suggest that histone H1 expression is associated with the Gleason pattern, cell proliferation and androgen receptor expression in prostate cancers.Pathology International 02/2012; 62(2):84-92. · 1.59 Impact Factor
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ABSTRACT: Elucidating the mechanisms of metastasis in prostate cancer, particularly to the bone, is a major issue for treatment of this malignancy. We previously reported that an androgen-independent variant had higher expression of glutathione S-transferase pi (Gst-pi) compared with a parent androgen-dependent transplantable rat prostate carcinoma which was established from the transgenic rat for adenocarcinoma of the prostate (TRAP). A new cell line, PCai1, was established from the androgen-independent tumor and investigated its metastatic potential in nude mice. The tumorigenesis of PCai1 cells in vivo was studied by subcutaneous transplantations into nude mice. The growth in the microenvironment of the prostate was studied by orthotopic transplantation of PCai1 cells into nude mice. The metastatic potential of PCai1 cells was studied by tail vein injections. Effects of Gst-pi knocked down were analysis in PCai1 cells. PCai1 frequently formed metastatic lesions in the lung and lymph nodes after orthotopic implantation in the prostate. Intravenous injections of PCai1, metastasis to lung and bone were obvious. PCai1 had strong expression for Gst-pi, therefore we tried knocked down Gst-pi. Gst-pi-siRNA in vitro significantly suppressed cell proliferation rate. In addition, high levels of intracellular reactive oxygen species (ROS) were recognized in the Gst-pi knockout. Gst-pi expression of the prostate cancers are dependent on metastatic site, and that Gst-pi has an important role in adapting prostate cancer for growth and metastasis involving an alteration of ROS signals.The Prostate 07/2011; 72(5):533-41. · 3.57 Impact Factor
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ABSTRACT: Protein kinase D (PKD) acts as a major mediator of several signaling pathways related to cancer development. Aberrant PKD expression and activity have been shown in multiple cancers, and novel PKD inhibitors show promising anticancer activities. Despite these advances, the mechanisms through which PKD contributes to the pathogenesis of cancer remain unknown. Here, we establish a novel role for PKD3, the least studied member of the PKD family, in the regulation of prostate cancer cell growth and motility through modulation of secreted tumor-promoting factors. Using both a stable inducible knockdown cell model and a transient knockdown system using multiple siRNAs, we show that silencing of endogenous PKD3 significantly reduces prostate cancer cell proliferation, migration, and invasion. In addition, conditioned medium from PKD3-knockdown cells exhibits less migratory potential compared with that from control cells. Further analysis indicated that depletion of PKD3 blocks secretion of multiple key tumor-promoting factors including matrix metalloproteinase (MMP)-9, interleukin (IL)-6, IL-8, and GROα but does not alter mRNA transcript levels for these factors, implying impairment of the secretory pathway. More significantly, inducible depletion of PKD3 in a subcutaneous xenograft model suppresses tumor growth and decreases levels of intratumoral GROα in mice. These data validate PKD3 as a promising therapeutic target in prostate cancer and shed light on the role of secreted tumor-promoting factors in prostate cancer progression.Molecular Cancer Therapeutics 04/2012; 11(7):1389-99. · 5.60 Impact Factor