Syndecan-1 (CD138) Suppresses Apoptosis in Multiple Myeloma by Activating IGF1 Receptor: Prevention by SynstatinIGF1R Inhibits Tumor Growth
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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.
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The HS chain of SDC1 acts as a co-receptor for growth factors, promoting activation of several RTKs such as EGFR, c-MET, FGFR, and IGF1R.
“The HS chain of SDC1 has been shown to act as a co-receptor for growth factors, promoting the activation of several RTKs, such as EGFR, c-MET, FGFR, and IGF1R.29,30,31,32”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [29]
The Results section ('Sdc1-coupled IGF1R comprises both constitutively active and IGF1-stimulated fractions'; page unavailable) shows that IGF1R activation depends on coupling to SDC1. The Introduction describes an extracellular-domain capture motif, but our copy does not establish that the HS chain acts as the growth-factor co-receptor, nor does it show SDC1 promoting activation of EGFR, c-MET, or FGFR. (LLM, conf=0.86)
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References 63 · Cited by 70
Research works printed but not linked: 3
- [7]Jung O Trapp-Stamborski V Purushothaman A Jin H Wang H Sanderson RD 2016 Heparanase-induced shedding of syndecan-1 promotes VEGFR2 activation and an invasive phenotype in multiple myeloma Oncogenesis in press PMC5154350 26926788
- [24]Rapraeger AC Ell BJ Roy M Li X Morrison OR Thomas GM 2013 Vascular endothelial-cadherin stimulates syndecan-1-coupled insulin-like growth factor-1 receptor and cross-talk between alphaVbeta3 integrin and vascular endothelial growth factor receptor 2 at the onset of endothelial cell dissemination during angiogenesis The FEBS journal 280 2194 2206 23331867 PMC3640762
- [30]Wang H Jin H Rapraeger AC 2015 Syndecan-1 and Syndecan-4 Capture Epidermal Growth Factor Receptor Family Members and the alpha3beta1 Integrin Via Binding Sites in Their Ectodomains: novel synstatins prevent kinase capture and inhibit alpha6beta4-integrin-dependent epithelial cell motility J Biol Chem 290 26103 26113 26350464 PMC4646262
- Authors
- Beauvais, D. M., Jung, O., Yang, Y., Sanderson, R. D., & Rapraeger, A. C.
- Affiliations
- University of Wisconsin–Madison (US)
- University of Alabama at Birmingham (US)
- Corresponding author
- Rapraeger, Alan C.
- Venue
- Cancer Research
- Published
- 2016-08-31
- Volume
- 76
- Issue
- 17
- Pages
- 4981-4993
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5010496
- OpenAlex
- W2460526988
- Cited by
- 70
- References
- 63
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 10 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 8 · 2019: 9 · 2018: 6 · 2017: 10 · 2016: 3
- FWCI
- 8.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01-CA139872, R01-CA118839, R01-CA163662, CA135075 and CA138340)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- syndecan-1, multiple myeloma, IGF-1 receptor, ASK1, apoptosis, peptide inhibitors, tumor angiogenesis, JNK signaling, caspase-3, plasma stability
- MeSH terms
- Animals, Antineoplastic Agents, Female, Flow Cytometry, Humans, Mice, Nude, Multiple Myeloma, Peptides, Apoptosis, Receptors, Somatomedin, Receptor, IGF Type 1, Cell Line, Tumor, Immunoprecipitation, MAP Kinase Kinase Kinase 5, Cell Proliferation, Mice, Syndecan-1, Gene Knockdown Techniques, Heterografts
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