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

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.

Pleiotropic Roles of Atrial Natriuretic Peptide in Anti-Inflammation and Anti-Cancer Activity

“…Prostate cancer cells secrete extracellular vesicles (EVs) loaded with pro-inflammatory molecules to modify the tumor microenvironment and promote tumor progression [ 76 ]. Mezzasoma et al reported that ANPs phosphorylated the NLRP3 receptor through the p38-MAPK pathway and then inhibited the inflammasome activation and IL-β maturation in PC3 cells, as well as reversing the inflammatory phenotypes of normal cells induced by EVs from PC3 cells [ 77 ].…”

Identification and validation of the pyroptosis-related genes signature based on immune microenvironment and molecular heterogeneity in prostate adenocarcinoma

“…TNF signaling pathway mediates enzalutamide induced metastatic phenotype of PRAD [32]. NOD-like receptor signaling pathway contributes to the establishment of PRAD microenvironment [33]. The above results suggested that 33 PRGs play an important role in the occurrence and development of PRAD.…”

MasR and pGCA receptor activation protects primary vascular smooth muscle cells and endothelial cells against oxidative stress via inhibition of intracellular calcium

“…Previous reports were referred to select the concentration of H 2 O 2 and peptides. The Oxidative stress was induced by exposing the primary VSMC cells to H 2 O 2 (100 µM) 27 in the presence or absence of Ang1‐7, BNP, NP (1 µM) 28–30 . Time points for further studies was selected on MTT assays.…”