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SUPPLEMENTARY FIGURE 2. SSTN inhibition of IGF1R in myeloma inhibits adhesion-independent cell survival. from Syndecan-1 (CD138) Suppresses Apoptosis in Multiple Myeloma by Activating IGF1 Receptor: Prevention by SynstatinIGF1R Inhibits Tumor Growth
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posted on 2023-03-31, 00:08 authored by DeannaLee M. Beauvais, Oisun Jung, Yang Yang, Ralph D. Sanderson, Alan C. RapraegerA. CAG cells are plated for 2 hr on VN or FN in the presence or absence of 10 μg/mL VLA-4 (P1H4) or 30 μg/mL αvβ5 (P1F6) integrin blocking antibodies; B. CAG myeloma cells grown for 72 hr in the presence of 10 μg/mL VLA-4 (P1H4) or 30 μg/mL αvβ5 (P1F6) integrin blocking antibodies, 10 μM AG538, or 30 μM SSTNIGF1R are quantified and graphed relative to no treatment (set to 1.0). Error bars = SEM.
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ARTICLE 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.Usage metrics
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AngiogenesisAngiogenesis inhibitors & stimulatorsAngiogenesis mechanismsEndothelial cell functionsCell Death And SenescenceEffectors of apoptosisReceptor-coupled signaling to apoptosisCell SignalingProtein serine-threonine kinasesProtein tyrosine kinasesDrug TargetsCell surface receptor drug targetsHematological CancersMyelomasSmall Molecule Agents
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