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.
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Atrial natriuretic peptide
Cysteine rich domain
Critical assessment of predicted interaction
Root means square deviation
Root means square fluctuation
Accessible surface area
Abraham MJ et al (2019) GROMACS User Manual version 2019
Altschul SF et al (1990) Basic local alignment search tool. J Mol Biol 215(3):403–410
Anastas JN, Moon RT (2013) WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 13(1):11
Arend RC et al (2013) The Wnt/β-catenin pathway in ovarian cancer: a review. Gynecol Oncol 131(3):772–779
Asad M et al (2014) FZD7 drives in vitro aggressiveness in Stem-A subtype of ovarian cancer via regulation of non-canonical Wnt/PCP pathway. Cell Death Dis 5(7):e1346
Biasini M et al (2014) SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 42(W1):W252–W258
Brenner BM et al (1990) Diverse biological actions of atrial natriuretic peptide. Physiol Rev 70(3):665–699
Clevers H (2006) Wnt/β-catenin signaling in development and disease. Cell 127(3):469–480
Comeau SR et al (2004) ClusPro: a fully automated algorithm for protein–protein docking. Nucleic Acids Res 32(suppl_2):W96–W99
Consortium U (2009) The universal protein resource (UniProt) in 2010. Nucleic Acids Res 38(suppl_1):D142–D148
DeLano WL (2002) Pymol: an open-source molecular graphics tool. CCP4 Newsletter on Protein Crystallography 40(1):82–92
Dijksterhuis J, Petersen J, Schulte G (2014) WNT/F rizzled signalling: receptor–ligand selectivity with focus on FZD-G protein signalling and its physiological relevance: IUPHAR Review 3. Br J Pharmacol 171(5):1195–1209
Dominguez C, Boelens R, Bonvin AM (2003) HADDOCK: a protein−protein docking approach based on biochemical or biophysical information. J Am Chem Soc 125(7):1731–1737
Fiser A, Šali A (2003) Modeller: generation and refinement of homology-based protein structure models. Methods in enzymology. Elsevier, Amsterdam, pp 461–491
Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-Pdb Viewer: an environment for comparative protein modeling. Electrophoresis 18(15):2714–2723
Gurney A et al (2012) Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci 109(29):11717–11722
He X-L, Dukkipati A, Garcia KC (2006) Structural determinants of natriuretic peptide receptor specificity and degeneracy. J Mol Biol 361(4):698–714
Hirai H et al (2019) Crystal structure of a mammalian Wnt–frizzled complex. Nat Struct Mol Biol 26(5):372
Huelsken J, Behrens J (2002) The Wnt signalling pathway. J Cell Sci 115(21):3977–3978
Janda CY et al (2012) Structural basis of Wnt recognition by Frizzled. Science 337(6090):59–64
Janin J et al (2003) CAPRI: a critical assessment of predicted interactions. Proteins: Struct Funct Bioinf 52(1):2–9
Kazi MM et al (2016) The potential of Wnt signaling pathway in cancer: a focus on breast cancer. Cancer Transl Med 2(2):55
Kemp CR et al (2007) Expression of Frizzled5, Frizzled7, and Frizzled10 during early mouse development and interactions with canonical Wnt signaling. Dev Dyn 236(7):2011–2019
Kim M et al (2008) Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells. J Hepatol 48(5):780–791
Kirikoshi H, Sekihara H, Katoh M (2001) Up-regulation of Frizzled-7 (FZD7) in human gastric cancer. Int J Oncol 19(1):111–115
Knappe S et al (2004) Identification of domain structures in the propeptide of corin essential for the processing of proatrial natriuretic peptide. J Biol Chem 279(33):34464–34471
Koller K, Goeddel D (1992) Molecular biology of the natriuretic peptides and their receptors. Circulation 86(4):1081–1088
Krishnamurthy N, Kurzrock R (2018) Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treat Rev 62:50–60
Kukic P et al (2013) Protein dielectric constants determined from NMR chemical shift perturbations. J Am Chem Soc 135(45):16968–16976
Kumar S et al (2014) Molecular dissection of Wnt3a-Frizzled8 interaction reveals essential and modulatory determinants of Wnt signaling activity. BMC Biol 12(1):44
Kumari R et al (2014) g_mmpbsa—a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 54(7):1951–1962
Laskowski RA (2001) PDBsum: summaries and analyses of PDB structures. Nucleic Acids Res 29(1):221–222
Lemak A, Balabaev N (1994) On the Berendsen thermostat. Mol Simul 13(3):177–187
Levin ER, Gardner DG, Samson WK (1998) Natriuretic peptides. N Engl J Med 339(5):321–328
Nile AH et al (2018) A selective peptide inhibitor of Frizzled 7 receptors disrupts intestinal stem cells. Nat Chem Biol 14(6):582
Nosé S, Klein ML (1983) Constant pressure molecular dynamics for molecular systems. Mol Phys 50(5):1055–1076
Ren W et al (2016) MicroRNA-613 represses prostate cancer cell proliferation and invasion through targeting Frizzled7. Biochem Biophys Res Commun 469(3):633–638
Serafino A, Pierimarchi P (2014) Atrial natriuretic peptide: a magic bullet for cancer therapy targeting Wnt signaling and cellular pH regulators. Curr Med Chem 21(21):2401–2409
Serafino A et al (2012) Anti-proliferative effect of atrial natriuretic peptide on colorectal cancer cells: evidence for an Akt-mediated cross-talk between NHE-1 activity and Wnt/β-catenin signaling. Biochimica et Biophysica Acta (BBA) 1822(6):1004–1018
Ueno K et al (2008) Frizzled-7 as a potential therapeutic target in colorectal cancer. Neoplasia (New York, NY) 10(7):697
van der Spoel D, Hess B (2011) GROMACS—the road ahead. Wiley Interdisc Rev: Comput Mol Sci 1(5):710–715
Vermeulen L et al (2010) Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 12(5):468–476
Vesely DL (2005) Atrial natriuretic peptides: anticancer agents. J Investig Med 53(7):360–365
Vriend G (1990) WHAT IF: a molecular modeling and drug design program. J Mol Graph 8(1):52–56
Wilkins MR, Redondo J, Brown LA (1997) The natriuretic-peptide family. The Lancet 349(9061):1307
Yang L et al (2011) FZD7 has a critical role in cell proliferation in triple negative breast cancer. Oncogene 30(43):4437–4446
Yoshida T et al (2018) Three-dimensional organoid culture reveals involvement of Wnt/β-catenin pathway in proliferation of bladder cancer cells. Oncotarget 9(13):11060
This research has been funded by the Research Council of Tarbiat Modares University, Tehran, Iran.
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Dehghanbanadaki, N., Taghdir, M. & Naderi-Manesh, H. Investigation of Atrial Natriuretic Peptide as A Competitive Inhibitory Candidate Against Wnt/β-Catenin Signalling: A Molecular Dynamics Approach. Int J Pept Res Ther 27, 353–363 (2021). https://doi.org/10.1007/s10989-020-10085-9
- Atrial natriuretic peptide
- Wnt signaling