PMID- 31108998
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 11
IP  - 5
DP  - 2019 May 17
TI  - RAC1B Suppresses TGF-beta1-Dependent Cell Migration in Pancreatic Carcinoma Cells 
      through Inhibition of the TGF-beta Type I Receptor ALK5.
LID - 10.3390/cancers11050691 [doi]
LID - 691
AB  - 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)-beta1-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-beta 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-beta1 
      stimulation. RAC1B KO also increased TGF-beta1-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-beta1-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-beta/SMAD3-driven 
      cellular responses, such as growth inhibition and cell motility.
FAU - Ungefroren, Hendrik
AU  - Ungefroren H
AUID- ORCID: 0000-0002-7552-2087
AD  - First Department of Medicine, University Hospital Schleswig-Holstein, Campus 
      Lubeck, D-23538 Lubeck, Germany. hendrik.ungefroren@uksh.de.
AD  - Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric 
      Surgery, University Hospital Schleswig-Holstein, Campus Kiel, D-24105 Kiel, 
      Germany. hendrik.ungefroren@uksh.de.
FAU - Otterbein, Hannah
AU  - Otterbein H
AD  - First Department of Medicine, University Hospital Schleswig-Holstein, Campus 
      Lubeck, D-23538 Lubeck, Germany. hannahotterbein@web.de.
FAU - Fiedler, Christian
AU  - Fiedler C
AD  - First Department of Medicine, University Hospital Schleswig-Holstein, Campus 
      Lubeck, D-23538 Lubeck, Germany. c.fiedler93@gmx.de.
FAU - Mihara, Koichiro
AU  - Mihara K
AUID- ORCID: 0000-0002-8927-060X
AD  - 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. mihara@ucalgary.ca.
FAU - Hollenberg, Morley D
AU  - Hollenberg MD
AD  - 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. mhollenb@ucalgary.ca.
FAU - Gieseler, Frank
AU  - Gieseler F
AUID- ORCID: 0000-0001-6409-3822
AD  - Department of Oncology, University Hospital Schleswig-Holstein, Campus Lubeck, 
      D-23538 Lubeck, Germany. frank.gieseler@uksh.de.
FAU - Lehnert, Hendrik
AU  - Lehnert H
AD  - First Department of Medicine, University Hospital Schleswig-Holstein, Campus 
      Lubeck, D-23538 Lubeck, Germany. hendrik.lehnert@uni-luebeck.de.
FAU - Witte, David
AU  - Witte D
AD  - First Department of Medicine, University Hospital Schleswig-Holstein, Campus 
      Lubeck, D-23538 Lubeck, Germany. davidwittemail@gmail.com.
LA  - eng
GR  - PJT148565 to M.D.H./Canadian Institutes of Health Research/Canada
PT  - Journal Article
DEP - 20190517
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC6562819
OTO - NOTNLM
OT  - ALK5
OT  - CRISPR/Cas9
OT  - RAC1B
OT  - RNA interference
OT  - TGF-beta
OT  - cell migration
OT  - pancreatic carcinoma
COIS- The authors declare no conflict of interest.
EDAT- 2019/05/22 06:00
MHDA- 2019/05/22 06:01
PMCR- 2019/05/17
CRDT- 2019/05/22 06:00
PHST- 2019/04/04 00:00 [received]
PHST- 2019/05/10 00:00 [revised]
PHST- 2019/05/15 00:00 [accepted]
PHST- 2019/05/22 06:00 [entrez]
PHST- 2019/05/22 06:00 [pubmed]
PHST- 2019/05/22 06:01 [medline]
PHST- 2019/05/17 00:00 [pmc-release]
AID - cancers11050691 [pii]
AID - cancers-11-00691 [pii]
AID - 10.3390/cancers11050691 [doi]
PST - epublish
SO  - Cancers (Basel). 2019 May 17;11(5):691. doi: 10.3390/cancers11050691.