Comparison of epithelial mesenchymal transition mediated tyrosine kinase inhibitor resistance in non-small cell lung cancer cell lines with wild type EGFR and mutant type EGFR.

This study investigates the role of epithelial-mesenchymal transition (EMT) in the development of resistance against TKIs in NSCLC. Currently, the role of p120-catenin, Kaiso factor and PRMT-1 in reversal of EMT in T790M mutated and TKI-resistant NSCLC cells is a new line of study. In this investigation we found upregulation of cytoplasmic p120-catenin, and it was co-localized with Kaiso factor. In the nucleus, binding of p120-catenin to Kaiso factor initiates transcription by activating EMT-transcription factors such as Snail, Slug, Twist, and ZEB1. PRMT-1 was also found to be upregulated, which induces methylation of Twist and repression of E-cadherin activity, thus promoting EMT. We confirmed that TKI-resistant cells have mesenchymal cell type characteristics based on their cell morphology and gene or protein expression of EMT related proteins. EMT proteins, Vimentin and N-cadherin, displayed increased expression, whereas E-cadherin expression was downregulated. Finally, we found that the knockdown of p120-catenin and PRMT-1 by siRNA or use of a PRMT-1 inhibitor Furamidine increased Erlotinib sensitivity and could reverse EMT to overcome TKI resistance. PMID: 29337056 [PubMed - as supplied by publisher]
Source: Biochemical and Biophysical Research communications - Category: Biochemistry Authors: Tags: Biochem Biophys Res Commun Source Type: research