Department of Medicine and Surgery, University of Perugia, Polo Unico Sant'Andrea delle Fratte, P.le L. Severi, 1, 06132 Perugia, Italy.
Biomolecules. 2021 May 25;11(6):794. doi: 10.3390/biom11060794.
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.
炎症通过诱导促进肿瘤的微环境，是前列腺癌（PCa）进展的一个标志。NOD 样受体蛋白 3（NLRP3）-炎性小体激活、白细胞介素 1β（IL-1β）分泌和癌细胞释放的细胞外囊泡（EVs）有助于建立肿瘤微环境。我们已经表明，PC3 衍生的 EVs（PC3-EVs）在非癌性 PNT2 细胞中激活炎性小体级联反应。已知内源性生物分子和利钠肽（NPs），如 ANP 和 BNP，可抑制免疫细胞中的炎性小体激活。在这里，我们研究了 ANP 和 BNP 是否可以在体外改变 PCa 的炎症表型。我们使用 PNT2、LNCaP 和 PC3 细胞系，这些细胞系模拟不同的 PCa 进展阶段，通过 Western blot 分析炎性小体激活和相关途径，通过 ELISA 分析 IL-1β 分泌。我们发现，肿瘤进展的特征是组成性炎性小体激活、IL-1β 分泌增加和内源性 NPs 表达减少。通过 p38-MAPK 或 ERK1/2-MAPK 给予外源性 ANP 和 BNP，通过诱导 NLRP3 磷酸化，分别拮抗 PC3 和 PC3-EVs 处理的 PNT2 细胞中的炎性小体激活和 IL-1β 成熟。我们的结果表明，NPs 通过干扰细胞特异性信号通路，发挥多效性抗炎作用，汇聚到炎性小体磷酸化，表明 NPs 可以被纳入 PCa 的药物再利用过程。
