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A novel small-molecule MRCK inhibitor blocks cancer cell invasion
Authors:Unbekandt  Mathieu  Croft  Daniel R  Crighton  Diane  Mezna  Mokdad  McArthur  Duncan  McConnell  Patricia  Schüttelkopf  Alexander W  Belshaw  Simone  Pannifer  Andrew  Sime  Mairi  Bower  Justin  Drysdale  Martin  Olson  Michael F
Institution:1.INSERM, U1047, 186 Chemin du Carreau de Lanes, Nîmes, 30908, France
;2.INSERM U1047, Université Montpellier 1, UFR Médecine, 186 Chemin du Carreau de Lanes, Nîmes, 30908, France
;3.UMR 5086, BMSSI, CNRS- Université Lyon 1, Institut de Biologie et Chimie des Protéines, 7 Passage du Vercors, Lyon, F-69367, France
;4.Current address: Faculty of Engineering, Department of Food Engineering, Ege University, Bornova, 35100, Izmir, Turkey
;
Abstract:

Background

Dual oxidase maturation factor 1 (DUOXA1) has been associated with the maturation of the reactive oxygen species (ROS) producing enzyme, dual oxidase 1 (DUOX1) in the adult thyroid. However, ROS have also been implicated in the development of several tissues. We found that activated muscle satellite cells and primary myoblasts isolated from mice express robust levels of DUOXA1 and that its levels are altered as cells differentiate.

Results

To determine whether DUOXA1 levels affect muscle differentiation, we used an adenoviral construct (pCMV5-DUOXA1-GFP) to drive constitutive overexpression of this protein in primary myoblasts. High levels of DUOXA1 throughout myogenesis resulted in enhanced H2O2 production, fusion defects, reduced expression of early (myogenin) and late (myosin heavy chain) markers of differentiation, and elevated levels of apoptosis compared to control cells infected with an empty adenoviral vector (pCMV5-GFP). DUOXA1 knockdown (using a DUOXA1 shRNA construct) resulted in enhanced differentiation compared to cells subjected to a control shRNA, and subjecting DUOXA1 overexpressing cells to siRNAs targeting DUOX1 or apoptosis signal-regulating kinase 1 (ASK1) rescued the phenotype.

Conclusions

This study represents the first to demonstrate the importance of DUOXA1 in skeletal muscle myoblasts and that DUOXA1 overexpression in muscle stem cells induces apoptosis and inhibits differentiation through DUOX1 and ASK1.
Keywords:
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