Phosphodiesterase 3A: a new player in development of interstitial cells of Cajal and a prospective target in gastrointestinal stromal tumors (GIST).
2017
// Pierre Vandenberghe 1 , Perrine Hague 1 , Steven C. Hockman 2 , Vincent C. Manganiello 2, ** , Pieter Demetter 3 , Christophe Erneux 4, * and Jean-Marie Vanderwinden 1, * 1 Laboratory of Neurophysiology, Faculty of Medicine, Universite Libre de Bruxelles, Brussels, Belgium 2 Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA 3 Department of Pathology, Erasme University Hospital, Universite Libre de Bruxelles, Brussels, Belgium 4 IRIBHM, Faculty of Medicine, Universite 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 (IC 50 0.35 μM) and this effect synergized with imatinib (Chou-Talalay’s CI 50 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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