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RAC1B Suppresses TGF-β1-Dependent Cell Migration in Pancreatic Carcinoma Cells through Inhibition of the TGF-β Type I Receptor ALK5

1
First Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, D-23538 Lübeck, Germany
2
Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, D-24105 Kiel, Germany
3
Departments of Physiology and Pharmacology and Medicine, Inflammation Research Network, Snyder Institute for Chronic Diseases, University of Calgary, Cumming School of Medicine, Calgary, AB T2N 4N1, Canada
4
Department of Oncology, University Hospital Schleswig-Holstein, Campus Lübeck, D-23538 Lübeck, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(5), 691; https://doi.org/10.3390/cancers11050691
Received: 4 April 2019 / Revised: 10 May 2019 / Accepted: 15 May 2019 / Published: 17 May 2019
(This article belongs to the Special Issue TGF-Beta Signaling in Cancer)
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Abstract

The small GTPase Ras-related C3 botulinum toxin substrate 1B (RAC1B) has been shown previously by RNA interference-mediated knockdown (KD) to function as a powerful inhibitor of transforming growth factor (TGF)-β1-induced cell migration and epithelial-mesenchymal transition in epithelial cells, but the underlying mechanism has remained enigmatic. Using pancreatic carcinoma cells, we show that both KD and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-mediated knockout (KO) of RAC1B increased the expression of the TGF-β type I receptor ALK5 (activin receptor-like kinase 5), but this effect was more pronounced in CRISPR-KO cells. Of note, in KO, but not KD cells, ALK5 upregulation was associated with resensitization of TGFBR1 to induction by TGF-β1 stimulation. RAC1B KO also increased TGF-β1-induced C-terminal SMAD3 phosphorylation, SMAD3 transcriptional activity, growth inhibition, and cell migration. The KD of ALK5 expression by RNA interference or inactivation of the ALK5 kinase activity by dominant-negative interference or ATP-competitive inhibition rescued the cells from the RAC1B KD/KO-mediated increase in TGF-β1-induced cell migration, whereas the ectopic expression of kinase-active ALK5 mimicked this RAC1B KD/KO effect. We conclude that RAC1B downregulates the abundance of ALK5 and SMAD3 signaling, thereby attenuating TGF-β/SMAD3-driven cellular responses, such as growth inhibition and cell motility. View Full-Text
Keywords: RAC1B; ALK5; cell migration; pancreatic carcinoma; RNA interference; CRISPR/Cas9; TGF-β RAC1B; ALK5; cell migration; pancreatic carcinoma; RNA interference; CRISPR/Cas9; TGF-β
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Ungefroren, H.; Otterbein, H.; Fiedler, C.; Mihara, K.; Hollenberg, M.D.; Gieseler, F.; Lehnert, H.; Witte, D. RAC1B Suppresses TGF-β1-Dependent Cell Migration in Pancreatic Carcinoma Cells through Inhibition of the TGF-β Type I Receptor ALK5. Cancers 2019, 11, 691.

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