MDA-9/syntenin is a key regulator of glioma pathogenesis

Kegelman, Timothy P.; Das, Swadesh K.; Hu, Bin; Bacolod, Manny D.; Fuller, Christine; Menezes, Mitchell E.; Emdad, Luni; Dasgupta, Santanu; Baldwin, Albert S.; Bruce, Jeffrey N.; Dent, Paul; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B.

doi:10.1093/neuonc/not157

Cited by 53 publications

(107 citation statements)

References 46 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…MDA-9/Syntenin was shown previously to be a valuable target in addressing one of the deadliest aspects of GBM, its propensity to invade (14). Because radiation therapy has been demonstrated to induce invasion in GBM cells, targeting MDA-9/Syntenin could be a useful approach to complement conventional treatment.…”

Section: Mda-9/syntenin Inhibition Leads To Radiosensitization and Inmentioning

confidence: 99%

“…Because radiation therapy has been demonstrated to induce invasion in GBM cells, targeting MDA-9/Syntenin could be a useful approach to complement conventional treatment. Gliomas with higher expression of MDA-9/Syntenin are more likely to be high-grade, and patients whose tumors had high levels of MDA-9/Syntenin had a worse prognosis (14). With this in mind, we explored possible connections between MDA-9/Syntenin expression and radiotherapy in glioma using the Repository for Molecular Brain Neoplasia Data (REMBRANDT) database, a publicly available dataset with information on tumor gene expression, treatment history, and survival (https://gdoc.georgetown.edu/gdoc/).…”

Section: Mda-9/syntenin Inhibition Leads To Radiosensitization and Inmentioning

confidence: 99%

“…MDA-9/Syntenin amplifies Src and NF-κB signaling in melanoma and glioma (13,14,20). Src is a recognized enhancer of invasive signals in cancer settings, and has demonstrated involvement in postradiation signaling (19).…”

Section: Mda-9/syntenin Inhibition Leads To Radiosensitization and Inmentioning

confidence: 99%

“…Secreted factors significantly impact on cancer cell invasion, and MDA-9/Syntenin affects the secretion of important factors such as MMP-2 and VEGF in glioma (14). Radiation enhances the release of important enzymes, including those involved in invasion, such as the matrix metalloproteinase family (19).…”

Section: Epha2 Signaling Postradiation It Can Be Considered a Valuabmentioning

confidence: 99%

“…In addition to its roles in melanoma metastasis and tumor progression, MDA-9/Syntenin is highly expressed and involved in breast, gastric, and urothelial cell cancers (10,13). MDA-9/Syntenin is an important regulator of GBM invasion, angiogenesis, and tumor progression (14), and inhibiting MDA-9/Syntenin expression decreases GBM invasion (14,15) and enhances survival. Moreover, MDA-9/Syntenin is also overexpressed in glioma stem cells (GSCs), and is a regulator of GSC survival and stemness (16).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

Kegelman

Das

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

130

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is an intractable tumor despite therapeutic advances, principally because of its invasive properties. Radiation is a staple in therapeutic regimens, although cells surviving radiation can become more aggressive and invasive. Subtraction hybridization identified melanoma differentiation-associated gene 9 [MDA-9/Syntenin; syndecan-binding protein (SDCBP)] as a differentially regulated gene associated with aggressive cancer phenotypes in melanoma. MDA-9/Syntenin, a highly conserved double-PDZ domain-containing scaffolding protein, is robustly expressed in human-derived GBM cell lines and patient samples, with expression increasing with tumor grade and correlating with shorter survival times and poorer response to radiotherapy. Knockdown of MDA-9/Syntenin sensitizes GBM cells to radiation, reducing postradiation invasion gains. Radiation induces Src and EGFRvIII signaling, which is abrogated through MDA-9/Syntenin down-regulation. A specific inhibitor of MDA-9/Syntenin activity, PDZ1i (113B7), identified through NMR-guided fragment-based drug design, inhibited MDA-9/Syntenin binding to EGFRvIII, which increased following radiation. Both genetic (shmda-9) and pharmacological (PDZ1i) targeting of MDA-9/Syntenin reduced invasion gains in GBM cells following radiation. Although not affecting normal astrocyte survival when combined with radiation, PDZ1i radiosensitized GBM cells. PDZ1i inhibited crucial GBM signaling involving FAK and mutant EGFR, EGFRvIII, and abrogated gains in secreted proteases, MMP-2 and MMP-9, following radiation. In an in vivo glioma model, PDZ1i resulted in smaller, less invasive tumors and enhanced survival. When combined with radiation, survival gains exceeded radiotherapy alone. MDA-9/Syntenin (SDCBP) provides a direct target for therapy of aggressive cancers such as GBM, and defined small-molecule inhibitors such as PDZ1i hold promise to advance targeted brain cancer therapy.

show abstract

Section: Mda-9/syntenin Inhibition Leads To Radiosensitization and Inmentioning

confidence: 99%

Section: Mda-9/syntenin Inhibition Leads To Radiosensitization and Inmentioning

confidence: 99%

Section: Mda-9/syntenin Inhibition Leads To Radiosensitization and Inmentioning

confidence: 99%

Section: Epha2 Signaling Postradiation It Can Be Considered a Valuabmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

Kegelman

Das

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

130

View full text Add to dashboard Cite

show abstract

Melanoma differentiation associated gene‐9/syndecan binding protein promotes hepatocellular carcinoma

et al. 2023

Self Cite

View full text Add to dashboard Cite

Background and Aims: The oncogene Melanoma differentiation associated gene‐9/syndecan binding protein (MDA‐9/SDCBP) is overexpressed in many cancers, promoting aggressive, metastatic disease. However, the role of MDA‐9 in regulating hepatocellular carcinoma (HCC) has not been well studied. Approach and Results: To unravel the function of MDA‐9 in HCC, we generated and characterized a transgenic mouse with hepatocyte‐specific overexpression of MDA‐9 (Alb/MDA‐9). Compared with wild‐type (WT) littermates, Alb/MDA‐9 mice demonstrated significantly higher incidence of N‐nitrosodiethylamine/phenobarbital‐induced HCC, with marked activation and infiltration of macrophages. RNA sequencing (RNA‐seq) in naive WT and Alb/MDA‐9 hepatocytes identified activation of signaling pathways associated with invasion, angiogenesis, and inflammation, especially NF‐κB and integrin‐linked kinase signaling pathways. In nonparenchymal cells purified from naive livers, single‐cell RNA‐seq showed activation of Kupffer cells and macrophages in Alb/MDA‐9 mice versus WT mice. A robust increase in the expression of Secreted phosphoprotein 1 (Spp1/osteopontin) was observed upon overexpression of MDA‐9. Inhibition of NF‐κB pathway blocked MDA‐9–induced Spp1 induction, and knock down of Spp1 resulted in inhibition of MDA‐9–induced macrophage migration, as well as angiogenesis. Conclusions: Alb/MDA‐9 is a mouse model with MDA‐9 overexpression in any tissue type. Our findings unravel an HCC‐promoting role of MDA‐9 mediated by NF‐κB and Spp1 and support the rationale of using MDA‐9 inhibitors as a potential treatment for aggressive HCC.

show abstract

CRM197 in Combination With shRNA Interference of VCAM-1 Displays Enhanced Inhibitory Effects on Human Glioblastoma Cells

Lin

Wang

et al. 2015

J. Cell. Physiol.

View full text Add to dashboard Cite

CRM197 is a naturally nontoxic diphtheria toxin mutant that binds and inhibits heparin-binding epidermal growth factor-like growth factor. CRM197 serves as carrier protein for vaccine and other therapeutic agents. CRM197 also inhibits the growth, migration, invasion and induces apoptosis in various tumors. Vascular cell adhesion molecule-1 (VCAM-1) is an important cell surface adhesion molecule associated with malignancy of gliomas. In this work, we aimed to investigate the role and mechanism of CRM197 combined with shRNA interference of VCAM-1 (shRNA-VCAM-1) on the migration, invasion and apoptosis of glioblastoma cells. U87 and U251 human glioblastoma cells were treated with CRM197 (10 μg/ml) and shRNA interfering technology was employed to silence VCAM-1 expression. Cell viability, migration, invasiveness and apoptosis were assessed with CCK8, Transwell and Annexin V-PE/7-AAD staining. Activation of cleaved caspase-3, 8 and 9, activity of matrix metalloproteinase-2/9 (MMP-2/9) and expression of phosphorylated Akt (p-Akt) were also checked. Results showed that CRM197 and shRNA-VCAM-1 not only significantly inhibited the cell proliferation, migration, invasion, but also promoted the apoptosis of U87 and

show abstract

MDA-9/syntenin is a key regulator of glioma pathogenesis

Abstract: Our findings indicate that MDA-9/syntenin is a novel and important mediator of invasion in GBM and a key regulator of pathogenesis, and we identify it as a potential target for anti-invasive treatment in human astrocytoma.

Cited by 53 publications

References 46 publications

Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

Melanoma differentiation associated gene‐9/syndecan binding protein promotes hepatocellular carcinoma

CRM197 in Combination With shRNA Interference of VCAM-1 Displays Enhanced Inhibitory Effects on Human Glioblastoma Cells

Contact Info

Product

Resources

About