title: The C-terminal region Mesd peptide mimics full-length Mesd and acts as an inhibitor of Wnt/β-catenin signaling in cancer cells.
abstract: While Mesd was discovered as a specialized molecular endoplasmic reticulum chaperone for the Wnt co-receptors LRP5 and LRP6, recombinant Mesd protein is able to bind to mature LRP5 and LRP6 on the cell surface and acts as a universal antagonist of LRP5/6 modulators. In our previous study, we found that the C-terminal region of Mesd, which is absent in sequences from invertebrates, is necessary and sufficient for binding to mature LRP6 on the cell surface. In the present studies, we further characterized the interaction between the C-terminal region Mesd peptide and LRP5/6. We found that Mesd C-terminal region-derived peptides block Mesd binding to LRP5 at the cell surface too. We also showed that there are two LRP5/6 binding sites within Mesd C-terminal region which contain several positively charged residues. Moreover, we demonstrated that the Mesd C-terminal region peptide, like the full-length Mesd protein, blocked Wnt 3A- and Rspodin1-induced Wnt/β-catenin signaling in LRP5- and LRP6- expressing cells, suppressed Wnt/β-catenin signaling in human breast HS578T cells and prostate cancer PC-3 cells, and inhibited cancer cell proliferation, although the full-length Mesd protein is more potent than its peptide. Finally, we found that treatment of the full-length Mesd protein and its C-terminal region peptide significantly increased chemotherapy agent Adriamycin-induced cytotoxicity in HS578T and PC-3 cells. Together, our results suggest that Mesd C-terminal region constitutes the major LRP5/6-binding domain, and that Mesd protein and its C-terminal region peptide have a potential therapeutic value in cancer.
authors.affiliation: Drug Discovery Division, Southern Research Institute, Birmingham, Alabama, United States of America.
authors.forename: Cuihong
authors.initials: C
authors.lastname: Lin
authors.forename: Wenyan
authors.initials: W
authors.lastname: Lu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Angelina I
authors.initials: AI
authors.lastname: Londoño-Joshi
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism*; D008969:Molecular Sequence Data; D053244:Osteoprotegerin / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects*; D019699:Thrombospondins / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060509:Wnt3A Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D000098907:R-Spondins
chemical_list: D004317:Doxorubicin; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D018832:Molecular Chaperones; D053244:Osteoprotegerin; D010446:Peptide Fragments; D019699:Thrombospondins; D051153:Wnt Proteins; D060509:Wnt3A Protein; D051176:beta Catenin; C555482:LRP5 protein, human; C555475:LRP6 protein, human; C506348:MESD protein, human; C503243:RSPO1 protein, human; D000098907:R-Spondins