title: Syndecan-1 (CD138) Suppresses Apoptosis in Multiple Myeloma by Activating IGF1 Receptor: Prevention by SynstatinIGF1R Inhibits Tumor Growth.
abstract: Syndecan-1 (Sdc1/CD138) expression is linked to disease severity in multiple myeloma, although the causal basis for this link remains unclear. Here we report that capture of the IGF1 receptor (IGF1R) by Sdc1 suppresses ASK1-dependent apoptosis in multiple myeloma cells. Sdc1 binds two different fractions of IGF1R, one that is constitutively active and a second that is activated by IGF1 ligand. Notably, IGF1R kinase activity in both fractions is blocked by synstatinIGF1R (SSTNIGF1R), a peptide that inhibits IGF1R capture by Sdc1, as well as by a truncated peptide (SSTNIGF1R-T) that appears to be specific for multiple myeloma cells. Mechanistically, we show that ASK1 is bound to active IGF1R and inhibited by Tyr and Ser83/Ser966 phosphorylation. When IGF1R engagement with Sdc1 is blocked by SSTNIGF1R, ASK1 becomes activated, and initiates JNK- and caspase-3-mediated apoptosis. In pharmacologic tests, we find SSTNIGF1R is highly stable in human plasma and displays a half-life of 27 hours in mice, wherein it significantly reduces both the size and neovascularization of CAG myeloma tumor xenografts. Taken together, our results offer a preclinical proof of concept and mechanistic rationale for the exploration of SSTNIGF1R as an experimental therapeutic to dually attack multiple myeloma tumor cell survival and tumor angiogenesis. Cancer Res; 76(17); 4981-93. ©2016 AACR.
authors.affiliation: Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: DeannaLee M
authors.initials: DM
authors.lastname: Beauvais
authors.affiliation: Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin. The Graduate Program in Molecular and Cellular Pharmacology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Oisun
authors.initials: O
authors.lastname: Jung
authors.affiliation: Department of Pathology and the University of Alabama at Birmingham Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pathology and the University of Alabama at Birmingham Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Ralph D
authors.initials: RD
authors.lastname: Sanderson
authors.affiliation: Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin. The Graduate Program in Molecular and Cellular Pharmacology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin. The University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin. rapraeger@humonc.wisc.edu.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Rapraeger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000494:pharmacology*; D017451:Receptors, Somatomedin / Q000378:metabolism*; D053668:Syndecan-1 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C000597236:IGF1R protein, human; D010455:Peptides; D017451:Receptors, Somatomedin; C508241:SDC1 protein, human; D053668:Syndecan-1; D017526:Receptor, IGF Type 1; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human