Thus, EMT plays a key role in malignant progression and increase of severity of metastasis. As a result of these changes, the tumor cells lose their contacts with neighbor cells and basement membrane, acquire highly invasive properties and can disseminate to distant organs. Besides this, the events occurring during EMT also include the rearrangement of cytoskeleton (e.g., a switch from cytokeratins to vimentin), the acquisition of a spindle-shaped mesenchymal phenotype and the up-regulation of mesenchymal markers, such as neural cadherin (N-cadherin), fibronectin and vimentin.
Upon the activation of EMT, the expression of epithelial cadherin (E-cadherin), being the major component of the cell-cell adherens junctions, is markedly repressed, which causes the loss of epithelial cobblestone-like morphology. These cells can secrete an array of growth factors and cytokines, such as transforming growth factor β (TGF-β), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), interleukin 6 (IL-6) and others, which bind to the corresponding receptors exposed on the surface of tumor cells and thereby activate a complex network of signaling pathways with subsequent up-regulation of EMT-associated transcription factors ZEB1/2, Snail, Slug and Twist1/2 that orchestrate EMT program. ĮMT of tumor cells can be induced by different stimulus from tumor microenvironment, primarily the stromal cells, surrounding the malignant tissue, e.g., myeloid-derived suppressor cells, cancer-associated fibroblasts and macrophages. The acquisition of a mesenchymal phenotype by malignant cells via EMT and their subsequent dissemination and outgrowth at distant organs was shown not only for a wide range of epithelial tumors, including lung, breast, pancreatic, prostate, liver and other carcinomas, but also for melanoma and hematological malignancies. EMT is one of the key factors exerting a marked stimulation of tumor progression and metastasis, and weakening the sensitivity of tumor cells to chemo- and immunotherapy. Altogether, our data provided valuable information for a better understanding of the antitumor activity of cyano enone-bearing semisynthetic compounds and revealed SM as a promising anti-metastatic drug candidate.Įpithelial-mesenchymal transition (EMT) is a reversible process during which tumor cells lose their apical-basal polarity and contacts with adjacent cells, as well as acquire motile and invasive behavior.
The inhibitory effect of SM on EMT revealed in vitro was further confirmed in a metastatic model of murine B16 melanoma: SM was found to effectively block metastatic dissemination of melanoma B16 cells in vivo, increase expression of E-cadherin and suppress expression of MMP-9 in lung metastatic foci.
MOUSE BLOWJOB SIBERIAN MOUSE BLOWJOB FOTO RAFLAR SIBERIAN VERIFICATION
Network pharmacology analysis with subsequent verification by molecular modeling revealed that matrix metalloproteinases MMP-2/-9 and c-Jun N-terminal protein kinase 1 (JNK1) can be considered as hypothetical primary targets of SM, mediating its marked anti-EMT activity. Further study showed that SM effectively blocked transforming growth factor β (TGF-β)-induced epithelial-mesenchymal transition (EMT) of A549 cells: namely, inhibited TGF-β-stimulated motility and invasion of tumor cells as well as loss of their epithelial characteristics, such as, an acquisition of spindle-like phenotype, up- and down-regulation of mesenchymal (vimentin, fibronectin) and epithelial (E-cadherin, zona occludens-1 (ZO-1)) markers, respectively. Performed screening revealed SM as a hit compound, which inhibits motility of murine melanoma B16 and human lung adenocarcinoma A549 cells and significantly suppresses colony formation of A549 cells. In this work, we studied the effects of these compounds used in non-toxic dosage on the processes associated with metastatic potential of tumor cells. Moreover, GA derivative soloxolone methyl (SM) was found to induce ER stress and apoptosis in tumor cells in vitro and inhibit growth of carcinoma Krebs-2 in vivo. Previously, we showed that cyano enone-bearing derivatives of 18βH-glycyrrhetinic (GA) and deoxycholic acids displayed marked cytotoxicity in different tumor cell lines. Introduction of α-cyano α,β-unsaturated carbonyl moiety into natural cyclic compounds markedly improves their bioactivities, including inhibitory potential against tumor growth and metastasis.
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