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

Himanshu Arora, Kush Panara, Manish Kuchakulla, Shathiyah Kulandavelu, Kerry L. Burnstein, Andrew V. Schally, Joshua M. Hare, Ranjith Ramasamy

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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. Snitrosoglutathione (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.

Original languageEnglish (US)
Pages (from-to)11298-11303
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number44
DOIs
StatePublished - Oct 30 2018

Keywords

  • CRPC
  • Immunotherapy
  • Nitric oxide
  • Tumor microenvironment
  • Tumor-associated macrophages

ASJC Scopus subject areas

  • General

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