Cancers, Vol. 12, Pages 1545: RAC1B Induces SMAD7 via USP26 to Suppress TGF β1-Dependent Cell Migration in Mesenchymal-Subtype Carcinoma Cells

Cancers, Vol. 12, Pages 1545: RAC1B Induces SMAD7 via USP26 to Suppress TGFβ1-Dependent Cell Migration in Mesenchymal-Subtype Carcinoma Cells Cancers doi: 10.3390/cancers12061545 Authors: Hendrik Ungefroren Anuradha Kumarasinghe Melina Musfeldt Christian Fiedler Hendrik Lehnert Jens-Uwe Marquardt The small GTPase RAC1B has been shown to act as a powerful inhibitor of the transforming growth factor (TGF)β type I receptor ALK5 and TGFβ1/ALK5-induced epithelial–mesenchymal transition and cell motility. However, the precise mechanism has remained elusive. RNAi-mediated knockdown of RAC1B in the pancreatic ductal adenocarcinoma (PDAC)-derived cell line Panc1 failed to alter transcriptional activity from a transfected ALK5 promoter–reporter construct. In contrast, pharmacological inhibition of the proteasome decreased the abundance of ALK5 protein in cell lines of the mesenchymal subtype (Panc1, IMIM-PC-1, and breast cancer MDA-MB-231), but not in a PDAC cell line of the epithelial subtype (Colo357). Here, we focused on the inhibitory Smad protein, SMAD7, as a potential candidate for RAC1B-mediated inhibition of cell migration. In Panc1 cells devoid of RAC1B, SMAD7 protein was dramatically reduced and these cells were refractory to TGFβ1-induced upregulation of SMAD7 protein but not mRNA expression. Intriguingly, RNAi-mediated knockdown or ectopic overexpression of SMAD7 in Panc1 cells up- or down...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research