title: Kallistatin antagonizes Wnt/β-catenin signaling and cancer cell motility via binding to low-density lipoprotein receptor-related protein 6.
abstract: Kallistatin, a plasma protein, exerts pleiotropic effects in inhibiting angiogenesis, inflammation and tumor growth. Canonical Wnt signaling is the primary pathway for oncogenesis in the mammary gland. In this study, we demonstrate that kallistatin bound to the Wnt coreceptor low-density lipoprotein receptor-related protein 6 (LRP6), thus, blocking Wnt/β-catenin signaling and Wnt-mediated growth and migration in MDA-MB-231 breast cancer cells. Kallistatin inhibited Wnt3a-induced proliferation, migration, and invasion of cultured breast cancer cells. Moreover, kallistatin was bound to LRP6 in breast cancer cells, as identified by immunoprecipitation followed by western blot. Kallistatin suppressed Wnt3a-mediated phosphorylation of LRP6 and glycogen synthase kinase-3β, and the elevation of cytosolic β-catenin levels. Furthermore, kallistatin antagonized Wnt3a-induced expression of c-Myc, cyclin D1, and vascular endothelial growth factor. These findings indicate a novel role of kallistatin in preventing breast tumor growth and mobility by direct interaction with LRP6, leading to blockade of the canonical Wnt signaling pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Jingmei
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Yang
authors.forename: Pengfei
authors.initials: P
authors.lastname: Li
authors.forename: Grant
authors.initials: G
authors.lastname: Bledsoe
authors.forename: Lee
authors.initials: L
authors.lastname: Chao
authors.forename: Julie
authors.initials: J
authors.lastname: Chao
mesh_terms: D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D015843:Serpins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C555510:WNT3A protein, human; D060509:Wnt3A Protein; C051324:kallistatin; D019938:Cyclin D1