The scaffolding PDZ-domain containing protein MDA-9/syntenin is a tandem PDZ protein overexpressed in human melanoma, and breast and gastric cancer cells. MDA-9/syntenin affects cancer cell motility and invasion through distinct biochemical and signaling pathways, including focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK), resulting in activation of the NFκ B pathway. MDA9/syntenin also promotes melanoma metastasis by activating c-Src, but how c-Src regulates NFκ B activation is unclear. Using a human melanoma model, we document that MDA-9/syntenin/c-Src interactions are positive regulators of NFκ B activation. Inhibition of c-Src by PP2 treatment, by blocking c-Src or mda-9/syntenin expression with siRNA, or in c-Src (−/−) knockout cell lines, reduces NFκ B activation following overexpression of mda-9/syntenin or c-Src. Deletion or point mutations of the PDZ binding motif preventing MDA-9/syntenin association with c-Src reveals that both PDZ domains, with PDZ2 being the dominant module, are required for activating downstream signaling pathways, including p38 MAPK and NFκ B. We also document that MDA-9/syntenin/c-Src complexes functionally cooperate with NFκ B to promote anchorage-independent growth, motility and invasion of melanoma cells. These findings underscore PDZ domains of MDA-9/syntenin as promising potential therapeutic targets for intervening in a decisive component of cancer progression, namely metastatic tumor spread.
Background: MDA-9/syntenin and tissue factor (TF) are overexpressed in most types of human cancer. Results: Induction of MDA-9/syntenin in melanoma involves the binding of FVIIa and FX to TF on the cell surface, which initiates a signaling circuit essential for cell motility and metastasis of melanoma. Conclusion: MDA-9/syntenin is an important TF-regulated gene. Significance: Targeting TF-mediated MDA-9/syntenin may represent a novel therapeutic strategy for eliminating cancer.
Normal adult A strain mice are resistant to MHV3 infection. A strain mice immunosuppressed by 600 rads of x-irradiation or by anti-lymphocyte serum treatment became susceptible to the virus and died with specific lesions of the liver and high virus titers. However, mice immunized with MHV3 before sublethal x-irradiation resisted a second injection of virus. Resistant adult (A × C3H) F1 hybrids undergoing graft-vs-host (GVH) reaction became highly susceptible to MHV3 injected 8 days after parental cell injection. Virus titer 3 days after injection was 2 logs higher in mice undergoing GVH than in controls. However F1 hybrid mice resisted virus challenge when the first injection of virus was given 2 weeks before GVH induction. In addition, thymectomy also modified the behavior of resistant animals toward virus infection. It appears, therefore, that cell-mediated immune functions play an important role in resistance of mice to MHV3.
Humoral and cell-mediated immune responses were studied in resistant and susceptible strains of mice infected with mouse hepatitis virus type III (MHV3). Virus was maintained by regular passages in susceptible DBA/2 mice and assayed in DBA/2 mice by LD50 determination. Normal resistant A strain mice were able to clear the virus from liver, brain, and serum within 7 days after infection. No neutralizing antibody was found. Transfer of serum from immunized A strain mice was not effective in protecting susceptible DBA/2 mice against challenge with virus. In A strain animals resistance to MHV3 developed rapidly during the 3rd week of life. During the period of susceptibility, newborns were protected neither by transplacental passages of anti-MHV3 antibodies nor by injection of “educated” thymus cells. These results suggest that the development of resistance to MHV3 infection in mice cannot be explained solely on the basis of humoral or cell-mediated immunity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.