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Open AccessArticle

A-Kinase Anchoring Proteins Diminish TGF-β1/Cigarette Smoke-Induced Epithelial-To-Mesenchymal Transition

1
University of Groningen, Department of Molecular Pharmacology, 9713AV Groningen, The Netherlands
2
University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, GRIAC, 9713AV Groningen, The Netherlands
3
Institute of Experimental Cardiovascular Research, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
4
University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology Groningen, 9713AV Groningen, The Netherlands
5
University of Groningen, University Medical Center Groningen, Department of Pulmonology, 9713AV Groningen, The Netherlands
6
Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, 9713AV Groningen, The Netherlands
7
Palm Beach Atlantic University, Lloyd L. Gregory School of Pharmacy, Department of Pharmaceutical Sciences, West Palm Beach, FL 33401, USA
8
German Center for Cardiovascular Research (DZHK), 20246 Hamburg, Germany
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 356; https://doi.org/10.3390/cells9020356
Received: 29 October 2019 / Revised: 29 January 2020 / Accepted: 31 January 2020 / Published: 3 February 2020
(This article belongs to the Special Issue New Advances in Cyclic AMP Signalling)
Epithelial-to-mesenchymal transition (EMT) plays a role in chronic obstructive pulmonary diseases (COPD). Cyclic adenosine monophosphate (cAMP) can inhibit transforming growth factor-β1 (TGF-β1) mediated EMT. Although compartmentalization via A-kinase anchoring proteins (AKAPs) is central to cAMP signaling, functional studies regarding their therapeutic value in the lung EMT process are lacking. The human bronchial epithelial cell line (BEAS-2B) and primary human airway epithelial (pHAE) cells were exposed to TGF-β1. Epithelial (E-cadherin, ZO-1) and mesenchymal markers (collagen Ӏ, α-SMA, fibronectin) were analyzed (mRNA, protein). ELISA measured TGF-β1 release. TGF-β1-sensitive AKAPs Ezrin, AKAP95 and Yotiao were silenced while using siRNA. Cell migration was analyzed by wound healing assay, xCELLigence, Incucyte. Prior to TGF-β1, dibutyryl-cAMP (dbcAMP), fenoterol, rolipram, cilostamide, and forskolin were used to elevate intracellular cAMP. TGF-β1 induced morphological changes, decreased E-cadherin, but increased collagen Ӏ and cell migration, a process that was reversed by the inhibitor of δ/epsilon casein kinase I, PF-670462. TGF-β1 altered (mRNA, protein) expression of Ezrin, AKAP95, and Yotiao. St-Ht31, the AKAP antagonist, decreased E-cadherin (mRNA, protein), but counteracted TGF-β1-induced collagen Ӏ upregulation. Cigarette smoke (CS) increased TGF-β1 release, activated TGF signaling, augmented cell migration, and reduced E-cadherin expression, a process that was blocked by TGF-β1 neutralizing antibody. The silencing of Ezrin, AKAP95, and Yotiao diminished TGF-β1-induced collagen Ӏ expression, as well as TGF-β1-induced cell migration. Fenoterol, rolipram, and cilostamide, in AKAP silenced cells, pointed to distinct cAMP compartments. We conclude that Ezrin, AKAP95, and Yotiao promote TGF-β1-mediated EMT, linked to a TGF-β1 release by CS. AKAP members might define the ability of fenoterol, rolipram, and cilostamide to modulate the EMT process, and they might represent potential relevant targets in the treatment of COPD.
Keywords: epithelial-to-mesenchymal transition; TGF-β1; cAMP; A-kinase anchoring protein; Ezrin; AKAP95; Yotiao; cigarette smoke; COPD epithelial-to-mesenchymal transition; TGF-β1; cAMP; A-kinase anchoring protein; Ezrin; AKAP95; Yotiao; cigarette smoke; COPD
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MDPI and ACS Style

Zuo, H.; Trombetta-Lima, M.; Heijink, I.H.; van der Veen, C.H.; Hesse, L.; Faber, K.N.; Poppinga, W.J.; Maarsingh, H.; Nikolaev, V.O.; Schmidt, M. A-Kinase Anchoring Proteins Diminish TGF-β1/Cigarette Smoke-Induced Epithelial-To-Mesenchymal Transition. Cells 2020, 9, 356.

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