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

Abstract

The atrial natriuretic peptide (ANP), a cardiovascular hormone, plays a pivotal role in the homeostatic control of blood pressure, electrolytes, and water balance and is approved to treat congestive heart failure. In addition, there is a growing realization that ANPs might be related to immune response and tumor growth. The anti-inflammatory and immune-modulatory effects of ANPs in the tissue microenvironment are mediated through autocrine or paracrine mechanisms, which further suppress tumorigenesis. In cancers, ANPs show anti-proliferative effects through several molecular pathways. Furthermore, ANPs attenuate the side effects of cancer therapy. Therefore, ANPs act on several hallmarks of cancer, such as inflammation, angiogenesis, sustained tumor growth, and metastasis. In this review, we summarized the contributions of ANPs in diverse aspects of the immune system and the molecular mechanisms underlying the anti-cancer effects of ANPs.

Keywords: anti-cancer agent; atrial natriuretic peptide; heart hormone; inflammation; polypeptide.

Figure 1

Schematic representation of human atrial natriuretic peptide gene structure and biosynthetic process. (A) biosynthetic process of ANPs. (B) primary structure of ANPs.

Figure 2

Diagram representing the downstream effects of ANPs and NPRs. ANPs bind to the extracellular ligand-binding domain (ECD) of NPRA, causing conformational change and phosphorylation of the intracellular protein-kinase homology domain (KHD), which then stimulates the guanylate cyclase catalytic domain (GCD) to convert GTP into cGMP, while the production of cGMP activates downstream effectors, such as protein kinases. ANPs bind to the ECD of NPRC to activate the inhibitory guanine nucleotide regulatory protein activator (Gαi) domain, thereby inhibiting adenylate cyclase activity and activating phospholipase C (PLC).

Figure 3

Immunomodulatory effects of ANPs. ANPs potentiate superoxide anion secretion, ROS production, and the mobilization of prime polymorphonuclear neutrophils (PMNs); ANPs tightly regulate the activity of macrophages, enhancing phagocytic activity and ROS production on the one hand, while reducing the production of NO and pro-inflammatory cytokines (iNOS, COX-2, TNFα, NF-κB, and IL-1β) and inhibiting inflammasome activation on the other hand. ANPs increase phagocytosis, cell activity, and the IFN-α release of nature killer (NK) cells; ANPs regulate maturation and differentiation of dendric cells (DCs) and promote anti-inflammatory cytokine (IL-10) release, but they inhibit pro-inflammatory cytokine (IL-12 and TNF-α) secretion. For adaptive immunity, ANPs decrease the percentage of CD4⁺CD8⁺ thymocytes and increase the CD4⁻CD8⁻ cell population. In addition, ANPs alter DC differentiation and subsequently polarize naive CD4⁺ cells toward the Th2 or Th17 phenotypes. ANPs protect endothelial barrier function, prevent leakage, alter chemoattraction and cell adhesion, and inhibit endothelial activation. ANPs counteract the occurrence of inflammation and inflammasome activation in the tumor microenvironment (TME), as well as inhibiting perioperative systemic inflammation and suppressing pre-metastatic niche formation.

Figure 4

Roles of ANPs in cancer. ANPs exert antineoplastic potential by inhibiting the conversion of GDP-RAS to GTP-RAS, the RAS-MEK1/2-ERK1/2 kinase cascade, and cross-talk between the RAS-MEK1/2-ERK1/2 kinase cascade and VEGF, β-catenin, JNK, WNT, and STAT3. In addition, ANPs also modulate inflammation, ROS production, KCNQ1, and MMP9 expression.