Inducible nitric oxide synthase activity is essential for inhibition of prostatic tumor growth by interferon-β gene therapy

Olson, Melissa V.; Lee, J; Zhang, F; Wang, A; Dong, Zhongyun

doi:10.1038/sj.cgt.7700941

Cited by 24 publications

(21 citation statements)

References 43 publications

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“…In addition, interferon (IFN)-beta gene therapy was found to inhibit prostatic growth in wild-type but not in iNOS-null mice (Olson et al, 2006). These results show that iNOS activity is able to produce anti-tumor activity.…”

Section: Discussionmentioning

confidence: 61%

Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression

et al. 2006

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Chronic inflammation increases the risk of cancer and many cancers, including prostate cancer, arise at sites of chronic inflammation. Inducible nitric oxide synthase (iNOS) is an enzyme dominantly expressed during inflammatory reactions. Although synthesis of high amounts of nitric oxide (NO) by iNOS has been demonstrated in pathophysiological processes, such as acute or chronic inflammation, autoimmune diseases or tumorigenesis, the role of iNOS activity in most of these diseases is poorly understood. Analysing prostate cancer biopsies by immunohistochemistry we found iNOS protein expression in tumor cells strongly paralleled by nitrotyrosine suggesting that iNOS is fully active. In vitro, NO inhibits androgen receptor-dependent promoter activity and prostate specific antigen production as well as DNAbinding activity of the androgen receptor (AR) in a concentration-dependent manner. Inhibition of the activity of androgen receptor-dependent reporter constructs is neither owing to diminished AR protein levels nor owing to an inhibition of its nuclear import. In addition, NO inhibits the proliferation of androgen receptor-positive prostate cancer cells significantly more efficiently than proliferation of androgen receptor-negative prostate cancer cells. In summary, our findings suggest that intratumoral iNOS activity favors development of prostate cancer cells that are able to proliferate androgen receptor-independently, thereby promoting prostate tumor progression.

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Section: Discussionmentioning

confidence: 61%

Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression

et al. 2006

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“…Apoptosis in paraffin-embedded tissue sections was determined by the terminal deoxynucleotidyl transferase -mediated dUTP nick end labeling (TUNEL) method using a kit from Promega Co. as detailed in our previous studies (12,25).…”

Section: Methodsmentioning

confidence: 99%

Smad3 Is Overexpressed in Advanced Human Prostate Cancer and Necessary for Progressive Growth of Prostate Cancer Cells in Nude Mice

Lee²,

Revelo³

et al. 2007

Clinical Cancer Research

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Purpose: The purpose of this study was to investigate the potential role of Smad3, a key mediator of transforming growth factor-h signaling, in progression of prostate cancer. Experimental Design: Expression of Smad proteins was determined in human prostate cancer tissue array and cell lines. Growth and metastasis of cells overexpressing dominant-negative Smad3 (Smad3D) were studied to determine its role in tumor progression in mice. Cell growth, apoptosis, and expression of angiogenic molecules in tumor lesions were studied to determine potential pathways that Smad3 promotes tumor progression. Results: Smad3 was overexpressed in human prostate cancer, which correlated with Gleason score and expression of proliferating cell nuclear antigen. Androgen-independent PC-3MM2 and DU145 cells expressed much higher levels of Smad3 than did androgen-dependent LNCaP, 22Rv1, and LAPC-4 cells. Overexpression of Smad3D in PC-3MM2 cells (PC-3MM2-Smad3D) had minimal direct effects on cell growth but attenuated effects of transforming growth factor-h1 on gene expression and cell growth. Overexpression of Smad3D did not significantly alter tumor incidence but reduced tumor growth rate and metastasis incidence. Most cells in the control tumors, but not PC-3MM2-Smad3D tumors, were positively stained by an antibody to proliferating cell nuclear antigen. Microvessels and expression of angiogenic molecule interleukin-8 were significantly reduced in tumors from PC-3MM2-Smad3D cells. PC-3MM2-Smad3D tumors also expressed lower levels of vascular endothelial growth factor and platelet-derived growth factor. Conclusions: These data suggest that Smad3, through regulating angiogenic molecule expression in tumor cells, is critical for progression of human prostate cancer.Transforming growth factor-h1 (TGF-h1) is overexpressed in prostate cancer, especially in advanced disease. It has been shown that overexpression of TGF-h1 in prostate cancer tissues and high urinary and serum levels of TGF-h1 are associated with enhanced tumor angiogenesis and tumor metastasis, and poor clinical outcome (1 -3). TGF-h1 induces biological effects through a family of type I and type II transmembrane serine/ threonine kinase receptors. On interaction with TGF-h1, TGF-h receptor (ThR) II recruits ThRI, leading to phosphorylation and activation of ThRI. With the assistance of adapter proteins, ThRI binds the receptor-regulated Smads (Smad2 and/or Smad3) and phosphorylates the Smads at their COOH-terminal SSXS motif. The phosphorylated Smad2 or Smad3 will then associate with the common Smad4, translocate into the nucleus, bind to concatamers of a CAGA sequence (Smadbox), and activate target gene expression through interaction with other transcription factors, such as activator protein-1 and forkhead activin signal transducers (4, 5). TGF-h1 also induces gene transcription through Smad-independent pathways (6). As such, TGF-h1 stimulates TGF-h -activated kinase 1, via TGF-h -activated kinase 1 binding protein 1, and leads to the activation of transcription ...

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“…These experiments concluded that TRAMP-C2 cells are not suitable for carrying out studies proposed. We then tested effects of our novel therapy system on growth of TRAMP-C2RE3 tumors, which, also derived from TRAMP-C2 and grow slightly slower than TRAMP-L5, have been used in one of our recent publications in study adenoviral vector-mediated IFN-β gene therapy (1). We found that efficacy of H5BVIFN-β therapy against TRAMP-C2RE3 tumors ( Fig.…”

Section: Introductionmentioning

confidence: 99%

A Novel Therapy System for the Treatment of Occult Prostate Cancer

Dong¹

2006

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Inducible nitric oxide synthase activity is essential for inhibition of prostatic tumor growth by interferon-β gene therapy

Cited by 24 publications

References 43 publications

Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression

Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression

Smad3 Is Overexpressed in Advanced Human Prostate Cancer and Necessary for Progressive Growth of Prostate Cancer Cells in Nude Mice

A Novel Therapy System for the Treatment of Occult Prostate Cancer

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