1. Prevention of epithelial to mesenchymal transition in colorectal carcinoma by regulation of the E-cadherin-β-catenin-vinculin axis.
- Author
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Pal, Ipsita, Rajesh, Y., Banik, Payel, Dey, Goutam, Dey, Kaushik Kumar, Bharti, Rashmi, Naskar, Deboki, Chakraborty, Sandipan, Ghosh, Sudip K., Das, Swadesh K., Emdad, Luni, Kundu, Subhas Chandra, Fisher, Paul B., and Mandal, Mahitosh
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CADHERINS , *FOCAL adhesions , *CELL membranes , *CARCINOMA , *CELL migration , *GOVERNMENT regulation - Abstract
Epithelial to mesenchymal transition (EMT) is compulsory for metastatic dissemination and is stimulated by TGF-β. Although targeting EMT has significant therapeutic potential, very few pharmacological agents have been shown to exert anti-metastatic effects. BI-69A11, a competitive Akt inhibitor, displays anti-tumor activity toward melanoma and colon carcinoma. This study provides molecular and biochemical insights into the effects of BI-69A11 on EMT in colon carcinoma cells in vitro and in vivo. BI-69A11 inhibited metastasis-associated cellular migration, invasion and adhesion by inhibiting the Akt-β-catenin pathway. The underlying mechanism of BI-69A11-mediated inhibition of EMT included suppression of nuclear transport of β-catenin and diminished phosphorylation of β-catenin, which was accompanied by enhanced E-cadherin-β-catenin complex formation at the plasma membrane. Additionally, BI-69A11 caused increased accumulation of vinculin in the plasma membrane, which fortified focal adhesion junctions leading to inhibition of metastasis. BI-69A11 downregulated activation of the TGF-β-induced non-canonical Akt/NF-κB pathway and blocked TGF-β-induced enhanced expression of Snail causing restoration of E-cadherin. Overall, this study enhances our understanding of the molecular mechanism of BI-69A11-induced reversal of EMT in colorectal carcinoma cells in vitro, in vivo and in TGF-β-induced model systems. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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