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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).
- 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.
- Subjects :
- Aged
Animals
Antineoplastic Agents pharmacology
Biomarkers, Tumor genetics
Cell Line, Tumor
Cell Survival drug effects
Cell Survival genetics
Cilostazol
Cyclic Nucleotide Phosphodiesterases, Type 3 genetics
Drug Synergism
Female
Gastrointestinal Stromal Tumors drug therapy
Gastrointestinal Stromal Tumors genetics
HEK293 Cells
Humans
Imatinib Mesylate pharmacology
Interstitial Cells of Cajal drug effects
Male
Mice, 129 Strain
Mice, Knockout
Middle Aged
Phosphodiesterase 3 Inhibitors pharmacology
Pyridazines pharmacology
Tetrazoles pharmacology
Biomarkers, Tumor metabolism
Cyclic Nucleotide Phosphodiesterases, Type 3 metabolism
Gastrointestinal Stromal Tumors metabolism
Interstitial Cells of Cajal metabolism
Subjects
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