Natriuretic Peptides Regulate Prostate Cells Inflammatory Behavior: Potential Novel Anticancer Agents for Prostate Cancer.

Letizia Mezzasoma,Ilaria Bellezza,Vincenzo Nicola Talesa,Egidia Costanzi

doi:10.3390/biom11060794

Abstract

Inflammation, by inducing a tumor-promoting microenvironment, is a hallmark for prostate cancer (PCa) progression. NOD-like receptor protein 3 (NLRP3)-inflammasome activation, interleukin-1β (IL-1β) secretion, and cancer cell-released extracellular vesicles (EVs) contribute to the establishment of tumor microenvironment. We have shown that PC3-derived EVs (PC3-EVs) activate inflammasome cascade in non-cancerous PNT2 cells. It is known that the endogenous biomolecules and Natriuretic Peptides (NPs), such as ANP and BNP, inhibit inflammasome activation in immune cells. Here we investigated whether ANP and BNP modify PCa inflammatory phenotype in vitro. By using PNT2, LNCaP, and PC3 cell lines, which model different PCa progression stages, we analyzed inflammasome activation and the related pathways by Western blot and IL-1β secretion by ELISA. We found that tumor progression is characterized by constitutive inflammasome activation, increased IL-1β secretion, and reduced endogenous NPs expression. The administration of exogenous ANP and BNP, via p38-MAPK or ERK1/2-MAPK, by inducing NLRP3 phosphorylation, counteract inflammasome activation and IL-1β maturation in PC3 and PC3-EVs-treated PNT2 cells, respectively. Our results demonstrate that NPs, by interfering with cell-specific signaling pathways, exert pleiotropic anti-inflammatory effects converging toward inflammasome phosphorylation and suggest that NPs can be included in a drug repurposing process for PCa.

Highlights

We found that the advanced stage prostate cancer PC3 cells, exhibit comparable nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) protein expression level but higher pro-IL-1β and active P-20 fragment of caspase-1 (Figure 1A–C), paralleled by doubled IL-1β secretion level after 48 h of culture (Figure 1D) compared to the androgen-sensitive LNCaP cells
We demonstrated that the Natriuretic Peptides (NPs): atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), through NLRP3 phosphorylation, inhibit constitutive- and extracellular vesicles (EVs)-induced inflammasome activation via different signaling pathways in prostate cell lines
We showed that PC3 cells, expressing the NPs receptor Natriuretic Peptide Receptor-1 (NPR-1), express neither ANP nor BNP, suggesting that advanced stage prostate cancer cells cannot experience an autocrine NPs-mediate signaling for the control of inflammasome activation

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Prostate cancer (PCa) is the second most common cause of cancer and the sixth cause of cancer death among men worldwide [1]. Localized PCa is usually treated with surgery or radiation, whereas androgen deprivation therapy represents the best therapeutic option for metastatic tumors. Initial regression is frequently followed by a tumor relapse into a castration resistant phenotype for which no therapeutic treatment is presently available [2,3]. Alongside the well-established factors involved in PCa, chronic inflammation, caused by virus or microbial infections, represents a hallmark of PCa development and progression, as well as of the development of androgen independence [4,5]

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