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The anticancer properties and mechanism of action of tablysin-15, the RGD-containing disintegrin, in breast cancer cells.
International Journal of Biological Macromolecules 2019 January 18
αv β3 integrin expressed on cancer cell surfaces is associated with important cancer hallmarks including survival and metastasis and is thus a potential anticancer drug target. Tablysin-15 contains the RGD motif and is a high-affinity αv β3 integrin antagonist. The aim of this study was to investigate the antitumor effect and mechanism of action of tablysin-15 against αv β3 integrin high-expressing breast cancer cell lines in vitro and in vivo. Tablysin-15 dose-dependently inhibited the proliferation, migration, and invasion of two breast cancer cell lines via the αv β3 integrin in vitro. Proliferation inhibition was attributable to G0/G1 phase cell cycle arrest rather than apoptosis or necrosis. Furthermore, tablysin-15 downregulated the activity and mRNA expression of MMP-2/-9, VEGF, and COX-2 but upregulated TIMP-1/-2 mRNA in both cell lines. Further, tablysin-15 suppressed the expression of CDK2, CDK6, cyclin D1, and cyclin E, the phosphorylation of FAK, Akt, GSK-3β, and ERK, and the nuclear translocation of NF-κB while increasing the expression of the CDK inhibitor p21waf1/C1 . Lastly, tablysin-15 provided effective antitumor protection in vivo. Thus, tablysin-15 inhibits the metastasis and proliferation of breast cancer cells through binding αv β3 integrin and blocking FAK-associated signaling pathways as well as nuclear translocation of NF-κB.
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