Wnt/β-catenin signaling, a highly evolutionary conserved pathway, is abnormally regulated in many human cancers. This pathway is one of the proposed mechanisms of atrial natriuretic peptide (ANP) anti-cancer effect. ANP which at first reported as a cardio hormone, inhibits proliferation of different cancer cell lines and tumor growth in vitro and in vivo respectively. Previous studies have shown a possibility of direct interaction between ANP and Frizzled (FZD), the main extracellular receptor of the pathway, and so a competition between ANP and Wnt for binding to this receptor. Here, using a molecular dynamics approach, we investigated this hypothesis validity and also the probable mechanism involved. We found three overlapping binding regions between ANP and Wnt3a carboxyl-terminal domain (CTD) on FZD7, but there is not any overlap with the large amino-terminal domain (NTD) of this protein. Based on the results derived from our study and the previous report on the intrinsic inhibitory potential of NTD subdomain against Wnt signalling and the conserved structure of Wnt-FZD complex architecture, we concluded that ANP is able to compete with Wnt CTD for binding to FZD that it can lead to incompletion of complex formation procedure between Wnt3a and FZD7. Finally, we introduce this peptide as a potential scaffold to design selective inhibitors against FZD-dependant cancers.

Wnt /β-catenin信号传导是一种高度进化的保守途径，在许多人类癌症中均受到异常调节。该途径是心钠素（ANP）抗癌作用的机制之一。首先报道为心脏激素的ANP分别在体外和体内抑制不同癌细胞系的增殖和肿瘤生长。先前的研究表明，ANP和毛躁（FZD）是该途径的主要细胞外受体之间直接相互作用的可能性，因此ANP和Wnt之间存在竞争与该受体结合的竞争。在这里，我们使用分子动力学方法研究了这一假设的有效性以及所涉及的可能机理。我们在FZD7的ANP和Wnt3a羧基末端结构域（CTD）之间发现了三个重叠的结合区域，但与该蛋白质的大氨基末端结构域（NTD）没有任何重叠。根据我们的研究结果和先前关于NTD子域对Wnt信号的内在抑制潜能以及Wnt-FZD复杂结构的保守结构的报道，我们得出结论，ANP能够与Wnt CTD竞争与FZD的结合。它可能导致Wnt3a和FZD7之间复杂的形成过程不完整。最后，我们将这种肽作为潜在的支架来设计针对FZD依赖性癌症的选择性抑制剂。我们得出的结论是，ANP能够与Wnt CTD竞争与FZD的结合，从而导致Wnt3a和FZD7之间复杂的形成过程不完全。最后，我们将这种肽作为潜在的支架来设计针对FZD依赖性癌症的选择性抑制剂。我们得出的结论是，ANP能够与Wnt CTD竞争与FZD的结合，从而导致Wnt3a和FZD7之间复杂的形成过程不完全。最后，我们将这种肽作为潜在的支架来设计针对FZD依赖性癌症的选择性抑制剂。