The Yin Yang Role of Nitric Oxide in Prostate Cancer

Nitric oxide (NO) is a ubiquitous signaling molecule in the human body with well-known roles in many different processes and organ systems. In cancer, the two-concentrations hypothesis of NO has dictated that low levels of NO are cancer promoting, while high levels of NO are protective against cancer. Although prostate cancer is a hormonally driven malignancy, research has been shifting away from androgen-responsive epithelial cells and evolving to focus on NO therapies, the tumor microenvironment (TME), and inflammation. NO is reported to be able to inhibit activity of the androgen receptor. This may prevent prostate growth, but low levels of NO could conversely select for castration-resistant prostate cells, creating an aggressive cancer phenotype. At high levels, nitrosative stress created from NO overproduction can be protective against prostate neoplasia. In this review, we discuss development and possibilities of NO-based therapies for prostate cancer.

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Alterations of tumor microenvironment by nitric oxide impedes castration-resistant prostate cancer growth

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812704115 ◽

2018 ◽

Vol 115 (44) ◽

pp. 11298-11303 ◽

Cited By ~ 5

Author(s):

Himanshu Arora ◽

Kush Panara ◽

Manish Kuchakulla ◽

Shathiyah Kulandavelu ◽

Kerry L. Burnstein ◽

...

Keyword(s):

Prostate Cancer ◽

Nitric Oxide ◽

Tumor Microenvironment ◽

Tumor Suppression ◽

Nitrosative Stress ◽

Locally Advanced ◽

Tumor Burden ◽

Castration Resistant Prostate Cancer ◽

No Donor ◽

Castration Resistant

Immune targeted therapy of nitric oxide (NO) synthases are being considered as a potential frontline therapeutic to treat patients diagnosed with locally advanced and metastatic prostate cancer. However, the role of NO in castration-resistant prostate cancer (CRPC) is controversial because NO can increase in nitrosative stress while simultaneously possessing antiinflammatory properties. Accordingly, we tested the hypothesis that increased NO will lead to tumor suppression of CRPC through tumor microenvironment. S-nitrosoglutathione (GSNO), an NO donor, decreased the tumor burden in murine model of CRPC by targeting tumors in a cell nonautonomous manner. GSNO inhibited both the abundance of antiinflammatory (M2) macrophages and expression of pERK, indicating that tumor-associated macrophages activity is influenced by NO. Additionally, GSNO decreased IL-34, indicating suppression of tumor-associated macrophage differentiation. Cytokine profiling of CRPC tumor grafts exposed to GSNO revealed a significant decrease in expression of G-CSF and M-CSF compared with grafts not exposed to GSNO. We verified the durability of NO on CRPC tumor suppression by using secondary xenograft murine models. This study validates the significance of NO on inhibition of CRPC tumors through tumor microenvironment (TME). These findings may facilitate the development of previously unidentified NO-based therapy for CRPC.

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Androgen biosynthesis in castration-resistant prostate cancer

Endocrine Related Cancer ◽

10.1530/erc-14-0109 ◽

2014 ◽

Vol 21 (4) ◽

pp. T67-T78 ◽

Cited By ~ 27

Author(s):

Trevor M Penning

Keyword(s):

Prostate Cancer ◽

Enzyme Inhibitors ◽

Molecular Medicine ◽

Adult Males ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Patient Will ◽

The Usa ◽

Fatal Form ◽

Low Levels

Prostate cancer is the second leading cause of death in adult males in the USA. Recent advances have revealed that the fatal form of this cancer, known as castration-resistant prostate cancer (CRPC), remains hormonally driven despite castrate levels of circulating androgens. CRPC arises as the tumor undergoes adaptation to low levels of androgens by either synthesizing its own androgens (intratumoral androgens) or altering the androgen receptor (AR). This article reviews the major routes to testosterone and dihydrotestosterone synthesis in CRPC cells and examines the enzyme targets and progress in the development of isoform-specific inhibitors that could block intratumoral androgen biosynthesis. Because redundancy exists in these pathways, it is likely that inhibition of a single pathway will lead to upregulation of another so that drug resistance would be anticipated. Drugs that target multiple pathways or bifunctional agents that block intratumoral androgen biosynthesis and antagonize the AR offer the most promise. Optimal use of enzyme inhibitors or AR antagonists to ensure maximal benefits to CRPC patients will also require application of precision molecular medicine to determine whether a tumor in a particular patient will be responsive to these treatments either alone or in combination.

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Loss of Somatostatin Receptor Subtype 2 in Prostate Cancer Is Linked to an Aggressive Cancer Phenotype, High Tumor Cell Proliferation and Predicts Early Metastatic and Biochemical Relapse

PLoS ONE ◽

10.1371/journal.pone.0100469 ◽

2014 ◽

Vol 9 (7) ◽

pp. e100469 ◽

Cited By ~ 11

Author(s):

Jan K. Hennigs ◽

Julia Müller ◽

Matti Adam ◽

Joshua M. Spin ◽

Emilia Riedel ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Tumor Cell ◽

Somatostatin Receptor ◽

Receptor Subtype ◽

Tumor Cell Proliferation ◽

Biochemical Relapse ◽

Aggressive Cancer ◽

Cancer Phenotype ◽

Somatostatin Receptor Subtype 2

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Extracellular Microenvironment in Patient-derived Hydrogel Organoids of Prostate Cancer Regulates Therapeutic Response

10.1101/2020.05.17.20104349 ◽

2020 ◽

Author(s):

Matthew J Mosquera ◽

Rohan Bareja ◽

Jacob M Bernheim ◽

Muhammad Asad ◽

Cynthia Cheung ◽

...

Keyword(s):

Prostate Cancer ◽

Inflammatory Cells ◽

Cellular Reprogramming ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Prostate Cells ◽

Synthetic Hydrogel ◽

Neuroendocrine Prostate Cancer ◽

Prostate Cancers ◽

Novel Target

Following treatment with androgen receptor (AR) pathway inhibitors, ~20% of prostate cancer patients progress by shedding their dependence on AR. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). Currently, no targeted therapies are available for CRPC-NEPCs. A major hurdle in the development of new therapies and treatment of CRPC-NEPC is the lack of accurate models to test candidate treatments. Such models would ideally capture components of the tumor microenvironment (TME) factors, which likely regulate the phenotypic, genetic, and epigenetic underpinnings of this aggressive subset. The TME is a complex system comprised not only of malignant prostate cells but also stromal and inflammatory cells and a scaffold of extracellular matrix (ECM). ECM proteins are implicated in the survival and progression of cancer and development of chemoresistance, while are equally integral to the development of prostate cancer organoids. Here, using a combination of patient tumor proteomics and RNA sequencing, we define putative ECM cues that may guide the growth of prostate tumors in patients. Using this molecular information, we developed synthetic hydrogels that recapitulate the tumor ECM. Organoids cultured in the synthetic hydrogel niches demonstrate that ECM subtypes regulate the morphology, transcriptome, and epigenetics hallmarks of CRPC-Adeno and CRPC-NEPC. CRPC-NEPC organoid showed a differential response to small molecule inhibitors of epigenetic repressor EZH2 and Dopamine Receptor D2 (DRD2), the latter being a novel target in CRPC-NEPC when grown in tumor-specific ECM. Finally, in those synthetic ECM niches where drug resistance was observed in CRPC-NEPCs, cellular reprogramming by a synergistic combination of EZH2 inhibitors with DRD2 antagonists inhibited tumor growth. The synthetic platform can provide a more realistic prostate-specific microenvironment and subsequently enable the development of effective targeted therapeutics for prostate cancers.

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