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

Authors :
Vandenberghe P
Hagué P
Hockman SC
Manganiello VC
Demetter P
Erneux C
Vanderwinden JM
Source :
Oncotarget [Oncotarget] 2017 Jun 20; Vol. 8 (25), pp. 41026-41043.
Publication Year :
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.

Details

Language :
English
ISSN :
1949-2553
Volume :
8
Issue :
25
Database :
MEDLINE
Journal :
Oncotarget
Publication Type :
Academic Journal
Accession number :
28454120
Full Text :
https://doi.org/10.18632/oncotarget.17010