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

Inflammation, by inducing a tumor-promoting microenvironment, is a hallmark for prostate cancer (PCa) progression. NOD-like receptor protein 3 (NLRP3)-inflammasome activation, interleukin-1 beta (IL-1 beta) 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-1 beta secretion by ELISA. We found that tumor progression is characterized by constitutive inflammasome activation, increased IL-1 beta 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-1 beta 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.

Automated summary

Inflammation plays a key role in the progression of prostate cancer (PCa), with NOD-like receptor protein 3 (NLRP3)-inflammasome activation, interleukin-1 beta (IL-1 beta) secretion, and cancer cell-released extracellular vesicles (EVs) contributing to the establishment of tumor microenvironment. Endogenous biomolecules and Natriuretic Peptides (NPs) such as ANP and BNP have been shown to inhibit inflammasome activation in immune cells. This study demonstrated that exogenous ANP and BNP can modulate the inflammatory phenotype of PCa by reducing inflammasome activation and IL-1 beta secretion.