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1.
Prostate ; 69(12): 1334-42, 2009 Sep 01.
Article in English | MEDLINE | ID: mdl-19517575

ABSTRACT

BACKGROUND: Paired homeobox 2 gene (PAX2) is a transcriptional regulator, aberrantly expressed in prostate cancer cells and its down-regulation promotes cell death in these cells. The molecular mechanisms of tumor progression by PAX2 over-expression are still unclear. However, it has been reported that angiotensin-II (A-II) induces cell growth in prostate cancer via A-II type 1 receptor (AT1R) and is mediated by the phosphorylation of mitogen activated protein kinase (MAPK) as well as signal transducer and activator of transcription 3 (STAT3). METHODS: Here we have demonstrated that A-II up-regulates PAX2 expression in prostate epithelial cells and prostate cancer cell lines resulting in increased cell growth. Furthermore, AT1R receptor antagonist losartan was shown to inhibit A-II induced PAX2 expression in prostate cancer. Moreover, analysis using pharmacological inhibitors against MEK1/2, ERK1/2, JAK-II, and phospho-STAT3 demonstrated that AT1R-mediated stimulatory effect of A-II on PAX2 expression was regulated in part by the phosphorylation of ERK1/2, JAK II, and STAT3 pathways. In addition, we have showed that down-regulation of PAX2 by an AT1R antagonist as well as JAK-II and STAT3 inhibitors suppress prostate cancer cell growth. RESULTS: Collectively, these findings show for the first time that the renin-angiotensin system (RAS) may promote prostate tumorigenesis via up-regulation of PAX2 expression. CONCLUSIONS: Therefore, PAX2 may be a novel therapeutic target for the treatment of carcinomas such as prostate cancer via the down-regulation of its expression by targeting the AT1R signaling pathways.


Subject(s)
Angiotensin II/physiology , PAX2 Transcription Factor/metabolism , Prostate/metabolism , Prostatic Neoplasms/metabolism , Receptor, Angiotensin, Type 2/metabolism , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II Type 2 Receptor Blockers , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Enzyme Inhibitors/pharmacology , Humans , Losartan/pharmacology , Male , Phosphorylation , Prostate/drug effects , Prostate/pathology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , RNA, Messenger/metabolism , Signal Transduction , Up-Regulation
2.
Mol Immunol ; 46(6): 1140-8, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19118900

ABSTRACT

Human beta defensin-1 (hBD1) is a component of the immune system which links the innate and adaptive immune responses. We have demonstrated that hBD1 induces rapid cytolysis of prostate cancer cells and that it may also possess tumor suppressive abilities. In addition, there is a high frequency of cancer-specific loss of hBD1 expression which further suggests its potential role in tumor progression. However, the factors responsible for the loss of hBD1 expression are not known. PAX2, a transcriptional regulator normally expressed during early development, has been implicated as an oncogene in carcinomas of the kidney, prostate, breast and ovary. It is known that expression of PAX2 in these tumor cells mediates the evasion of cell death through the suppression of cell death pathways involving the p53 tumor suppressor. However, we have demonstrated that knock-down of PAX2 expression results in cell death independent of p53 status, thus suggesting that additional cell death pathways are negatively regulated by PAX2. Here we describe a novel pathway in which PAX2 represses hBD1 expression through binding of the PAX2 homeodomain to the hBD1 promoter. Furthermore, knock-down of PAX2 expression results in the re-expression of hBD1, and subsequently prostate cancer cell death. These findings are the first to demonstrate that the PAX2 oncogene suppresses hBD1 expression in cancer and further implicate PAX2 as a novel therapeutic target for prostate cancer treatment.


Subject(s)
PAX2 Transcription Factor/metabolism , Prostatic Neoplasms/metabolism , beta-Defensins/metabolism , Cell Death/physiology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Humans , Male , Mutation , PAX2 Transcription Factor/genetics , Promoter Regions, Genetic
3.
J Cell Biochem ; 104(6): 2298-309, 2008 Aug 15.
Article in English | MEDLINE | ID: mdl-18561328

ABSTRACT

An unbiased cDNA expression phage library derived from bone-marrow endothelial cells was used to identify novel surface adhesion molecules that might participate in metastasis. Herein we report that reticulocalbin 1 (RCN1) is a cell surface-associated protein on both endothelial (EC) and prostate cancer (PCa) cell lines. RCN1 is an H/KDEL protein with six EF-hand, calcium-binding motifs, found in the endoplasmic reticulum. Our data indicate that RCN1 also is expressed on the cell surface of several endothelial cell lines, including human dermal microvascular endothelial cells (HDMVECs), bone marrow endothelial cells (BMEC), and transformed human bone marrow endothelial cells (TrHBMEC). While RCN1 protein levels were highest in lysates from HDMVEC, this difference was not statistically significant compared BMEC and TrHBMEC. Given preferential adhesion of PCa to bone-marrow EC, these data suggest that RCN1 is unlikely to account for the preferential metastasis of PCa to bone. In addition, there was not a statistically significant difference in total RCN1 protein expression among the PCa cell lines. RCN1 also was expressed on the surface of several PCa cell lines, including those of the LNCaP human PCa progression model and the highly metastatic PC-3 cell line. Interestingly, RCN1 expression on the cell surface was upregulated by tumor necrosis factor alpha treatment of bone-marrow endothelial cells. Taken together, we show cell surface localization of RCN1 that has not been described previously for either PCa or BMEC and that the surface expression on BMEC is regulated by pro-inflammatory TNF-alpha.


Subject(s)
Bone and Bones/cytology , Calcium-Binding Proteins/metabolism , Cell Membrane/drug effects , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Prostatic Neoplasms/pathology , Tumor Necrosis Factor-alpha/pharmacology , Blotting, Western , Calcium-Binding Proteins/genetics , Cell Line , Cell Membrane/metabolism , Flow Cytometry , Gene Expression Regulation/drug effects , Humans , Male , Microscopy, Confocal , Peptide Library , RNA, Messenger/genetics , RNA, Messenger/metabolism
4.
Transl Oncogenomics ; 3: 37-43, 2008 Mar 03.
Article in English | MEDLINE | ID: mdl-21566742

ABSTRACT

Prostate cancer is the second leading cause of cancer death among men in the United States of America. However, the molecular mechanisms underlying the disease remain largely unknown. Therefore, the identification of tumor specific molecules that serve as targets for the development of new cancer drugs is considered to be a major goal in cancer research. The mouse Engrailed-2 (En-2) gene, which is a homeobox-containing transcription factor was recently identified as a candidate oncogene in breast cancer. Here, we demonstrate that En-2 is over-expressed in human prostate cancer cells as compared to normal prostate epithelial cells. In addition, our data suggests that EN2 expression may be positively modulated by PAX2 transcription factor. Furthermore, down-regulation of EN2 expression by siRNA resulted in a decrease in PAX2 expression. We also provide evidence that down-regulation of EN2 expression causes a dramatic decrease in prostate cancer cell proliferation. Therefore, from our studies we conclude that En-2 is a candidate oncogene in prostate cancer and its PAX2-regulated expression contributes to prostate cancer cell growth.

5.
Mol Immunol ; 45(3): 839-48, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17868871

ABSTRACT

Although it is known that innate immunity is key for protecting the body against foreign agents such as bacteria, little is known about elements of the innate immune system that have anti-tumor activity. Human Beta Defensin-1 (hBD-1), an important component of the innate immune response, is lost at high frequencies in malignant prostatic tissue, while high levels of expression are maintained in adjacent benign regions. In prostate carcinoma, frequent genetic alterations occur in the 8p22-23 region and several studies indicate there may be multiple tumor suppressor genes present within this region. The high incidence of loss of hBD-1 expression in prostate cancer, along with its chromosomal location of 8p23.2, raised the possibility that it may play a role in tumor suppression. To gain insight as to its function in prostate cancer, hBD-1 was cloned and ectopically expressed in four prostate cancer cell lines. Induction of hBD-1 expression resulted in a decrease in cellular growth in DU145 and PC3 cells. However, hBD-1 has no effect on the growth of androgen receptor (AR) positive LNCaP prostate cancer cells, but was again growth suppressive to PC3 cells with ectopic AR expression (PC3/AR+). hBD-1 also caused rapid induction of cytolysis and caspase-mediated apoptosis in DU145 and PC3 prostate cancer cells. Although the regulation of hBD-1 was not addressed in this study, our preliminary data demonstrated that the pathways involved may include cMYC and PAX2. Data presented here are the first to provide evidence of its potential role in prostate cancer cell death.


Subject(s)
Apoptosis/immunology , Immunity, Innate , Prostatic Neoplasms/immunology , Tumor Suppressor Proteins/immunology , beta-Defensins/immunology , Apoptosis/genetics , Cell Death/genetics , Cell Death/immunology , Cell Line, Tumor , Chromosome Aberrations , Chromosomes, Human, Pair 8/genetics , Chromosomes, Human, Pair 8/immunology , Cloning, Molecular , Gene Expression , Gene Expression Regulation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/immunology , Humans , Immunity, Innate/genetics , Male , PAX2 Transcription Factor/genetics , PAX2 Transcription Factor/immunology , PAX2 Transcription Factor/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/immunology , Proto-Oncogene Proteins c-myc/metabolism , Tumor Suppressor Proteins/biosynthesis , Tumor Suppressor Proteins/genetics , beta-Defensins/biosynthesis , beta-Defensins/genetics
6.
Cancer Lett ; 248(2): 251-61, 2007 Apr 18.
Article in English | MEDLINE | ID: mdl-16996682

ABSTRACT

Inhibition of apoptosis is a critical pathophysiological factor that contributes to the development of prostate cancer. Recently, PAX2, a transcriptional regulator implicated in oncogenesis, has been demonstrated to be expressed by prostate cancer. However, its downstream molecular pathways for suppression of apoptosis, other than the tumor suppressor gene p53, have yet to be elucidated. Here, we examine the effects of inhibiting PAX2 expression by prostate cancer cells that differ in p53 gene status. These data collectively demonstrate that PAX2 inhibition results in cell death independent of p53, and that additional tumor suppressors or cell death pathways may be inhibited by PAX2 in prostate cancer cells.


Subject(s)
Cell Death/physiology , PAX2 Transcription Factor/biosynthesis , Prostatic Neoplasms/metabolism , Tumor Suppressor Protein p53/metabolism , Blotting, Western , Caspases/metabolism , Cell Line, Tumor , Humans , Male , Microscopy, Confocal , PAX2 Transcription Factor/antagonists & inhibitors , Prostatic Neoplasms/genetics , RNA, Small Interfering , Reverse Transcriptase Polymerase Chain Reaction
7.
Lab Invest ; 83(4): 501-5, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12695553

ABSTRACT

In a previous large-scale gene expression profiling study of renal epithelial neoplasms, human beta-defensin-1 (DEFB1) was found to be significantly down-regulated in conventional clear cell (renal) carcinoma. We have now completed an expanded expression analysis of this gene. We performed immunohistochemical analysis for the DEFB1 protein in clinical specimens of both renal cell carcinoma and prostate cancer. In a subset of prostate cancers, we performed laser capture microdissection and RT-PCR to correlate mRNA levels with protein levels. Overall, 82% of prostate cancers exhibit either complete loss of protein expression or only minimal expression, whereas the adjacent benign epithelium retained expression in all cases. Similarly, 90% of renal cell carcinomas show cancer-specific loss of DEFB1 protein. In the prostate cancer subset analysis, mRNA levels correlate with protein levels. We have thus demonstrated the cancer-specific down-regulation of DEFB1 in a large sample of prostatic and renal carcinomas and validated one of the key findings of previous cancer gene profiling studies of prostatic and renal neoplasia.


Subject(s)
Carcinoma, Renal Cell/genetics , Gene Expression Regulation, Neoplastic , Kidney Neoplasms/genetics , Prostatic Neoplasms/genetics , beta-Defensins/genetics , Carcinoma, Renal Cell/chemistry , Carcinoma, Renal Cell/pathology , DNA Primers/chemistry , DNA, Neoplasm/analysis , Dissection , Fluorescent Antibody Technique, Indirect , Humans , Kidney Neoplasms/chemistry , Kidney Neoplasms/pathology , Male , Micromanipulation , Prostatic Neoplasms/chemistry , Prostatic Neoplasms/pathology , RNA, Messenger/metabolism , RNA, Neoplasm/analysis , Reverse Transcriptase Polymerase Chain Reaction , beta-Defensins/analysis
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