Oncotarget

Research Papers:

Phosphodiesterase 3A: a new player in development of interstitial cells of Cajal and a prospective target in gastrointestinal stromal tumors (GIST)

Pierre Vandenberghe, Perrine Hagué, Steven C. Hockman, Vincent C. Manganiello, Pieter Demetter, Christophe Erneux _ and Jean-Marie Vanderwinden

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Oncotarget. 2017; 8:41026-41043. https://doi.org/10.18632/oncotarget.17010

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Abstract

Pierre Vandenberghe1, Perrine Hagué1, Steven C. Hockman2, Vincent C. Manganiello2,**, Pieter Demetter3, Christophe Erneux4,* and Jean-Marie Vanderwinden1,*

1Laboratory of Neurophysiology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium

2Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

3Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium

4IRIBHM, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium

*These authors have contributed equally to this work

**deceased

Correspondence to:

Christophe Erneux, email: cerneux@ulb.ac.be

Jean-Marie Vanderwinden, email: jmvdwin@ulb.ac.be

Keywords: transgenic mice, cilostazol, tissue array, KIT, cancer

Received: August 15, 2016    Accepted: March 25, 2017    Published: April 10, 2017

ABSTRACT

We previously identified phosphodiesterase 3A (PDE3A) as a marker for interstitial cells of Cajal (ICC) in adult mouse gut. However, PDE3A expression and function during gut development and in ICC-derived gastrointestinal stromal tumors (GIST) remained unknown. Here we found that PDE3A was expressed throughout ICC development and that ICC density was halved in PDE3A-deficient mice. In the human imatinib-sensitive GIST882 cell line, the PDE3 inhibitor cilostazol halved cell viability (IC50 0.35 μM) and this effect synergized with imatinib (Chou-Talalay’s CI50 0.15). Recently the compound 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP was found to be cytotoxic selectively for cells expressing both PDE3A and Schlafen12 (SLFN12) (de Waal L et al. Nat Chem Bio 2016), identifying a new, non-catalytic, role for PDE3A. 108 out of 117 (92%) of our human GIST samples displayed both PDE3A and SLFN12 immunoreactivity. GIST882 cells express both PDE3A and SLFN12 and DNMDP decreased their viability by 90%. Our results suggest a role for PDE3A during ICC development and open novel perspectives for PDE3A in targeted GIST therapy, on one hand by the synergism between imatinib and cilostazol, a PDE3 inhibitor already in clinical use for other indications, and, on the other hand, by the neomorphic, druggable, PDE3A-SLFN12 cytotoxic interplay.


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