cUMP hydrolysis by PDE3A

Berrisch, Stefan; Ostermeyer, Jessica; Kaever, Volkhard; Kälble, Solveig; Hilfiker‐Kleiner, Denise; Seifert, Roland; Schneider, Erich H.

doi:10.1007/s00210-016-1328-1

Cited by 7 publications

(2 citation statements)

References 37 publications

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“…The cyclic nucleotide phosphodiesterase, PDE3A, is well-characterized with regard to its ability to hydrolyze the phosphodiester bonds of cAMP and cGMP to regulate and limit cellular responses to G protein-coupled receptor activation (3). More recently, evidence has also arisen for a role in hydrolysis of cUMP (4). Conversely, very little is known regarding SLFN12 function, although it may play a role in cell proliferation or differentiation (5)(6)(7)(8).…”

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confidence: 99%

Mechanistic insights into cancer cell killing through interaction of phosphodiesterase 3A and schlafen family member 12

Schnitzler

Gao

et al. 2020

Journal of Biological Chemistry

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Cytotoxic molecules can kill cancer cells by disrupting critical cellular processes or by inducing novel activities. 6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP) is a small molecule that kills cancer cells by generation of novel activity. DNMDP induces complex formation between phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12) and specifically kills cancer cells expressing elevated levels of these two proteins. Here, we examined the characteristics and covariates of the cancer cell response to DNMDP. On average, the sensitivity of human cancer cell lines to DNMDP is correlated with PDE3A expression levels. However, DNMDP could also bind the related protein, PDE3B, and PDE3B supported DNMDP sensitivity in the absence of PDE3A expression. Although inhibition of PDE3A catalytic activity did not account for DNMDP sensitivity, we found that expression of the catalytic domain of PDE3A in cancer cells lacking PDE3A is sufficient to confer sensitivity to DNMDP, and substitutions in the PDE3A active site abolish compound binding. Moreover, a genome-wide CRISPR screen identified the aryl hydrocarbon receptor–interacting protein (AIP), a co-chaperone protein, as required for response to DNMDP. We determined that AIP is also required for PDE3A-SLFN12 complex formation. Our results provide mechanistic insights into how DNMDP induces PDE3A-SLFN12 complex formation, thereby killing cancer cells with high levels of PDE3A and SLFN12 expression.

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confidence: 99%

Mechanistic insights into cancer cell killing through interaction of phosphodiesterase 3A and schlafen family member 12

Schnitzler

Gao

et al. 2020

Journal of Biological Chemistry

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“…Moreover, the pyrimidine nucleoside uridine activates adenosine receptors (Yilmaz et al 2008). Thus, the non-canonical cyclic nucleotide cUMP, which is currently discussed as a potential second messenger (Seifert et al 2015;Berrisch et al 2017;Ostermeyer et al 2018;Scharrenbroich et al 2019), may as well be exported and degraded to biologically active products. Preliminary results suggest that first-and second messenger effects of cyclic nucleotides are highly dependent on the investigated cell type (Schneider et al 2015).…”

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confidence: 99%

Apoptotic and anti-proliferative effect of guanosine and guanosine derivatives in HuT-78 T lymphoma cells

Schneider

Hofmeister

Kälble

et al. 2020

Naunyn-Schmiedeberg's Arch Pharmacol

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The effects of 100 μM of 3′,5′-cGMP, cAMP, cCMP, and cUMP as well as of the corresponding membrane-permeant acetoxymethyl esters on anti-CD3-antibody (OKT3)-induced IL-2 production of HuT-78 cutaneous T cell lymphoma (Sézary lymphoma) cells were analyzed. Only 3′,5′-cGMP significantly reduced IL-2 production. Flow cytometric analysis of apoptotic (propidium iodide/annexin V staining) and anti-proliferative (CFSE staining) effects revealed that 3′,5′-cGMP concentrations > 50 μM strongly inhibited proliferation and promoted apoptosis of HuT-78 cells (cultured in the presence of αCD3 antibody). Similar effects were observed for the positional isomer 2′,3′-cGMP and for 2′,-GMP, 3′-GMP, 5′-GMP, and guanosine. By contrast, guanosine and guanosine-derived nucleotides had no cytotoxic effect on peripheral blood mononuclear cells (PBMCs) or acute lymphocytic leukemia (ALL) xenograft cells. The anti-proliferative and apoptotic effects of guanosine and guanosine-derived compounds on HuT-78 cells were completely eliminated by the nucleoside transport inhibitor NBMPR (S-(4-Nitrobenzyl)-6-thioinosine). By contrast, the ecto-phosphodiesterase inhibitor DPSPX (1,3-dipropyl-8-sulfophenylxanthine) and the CD73 ecto-5′-nucleotidase inhibitor AMP-CP (adenosine 5′-(α,β-methylene)diphosphate) were not protective. We hypothesize that HuT-78 cells metabolize guanosine-derived nucleotides to guanosine by yet unknown mechanisms. Guanosine then enters the cells by an NBMPR-sensitive nucleoside transporter and exerts cytotoxic effects. This transporter may be ENT1 because NBMPR counteracted guanosine cytotoxicity in HuT-78 cells with nanomolar efficacy (IC 50 of 25-30 nM). Future studies should further clarify the mechanism of the observed effects and address the question, whether guanosine or guanosinederived nucleotides may serve as adjuvants in the therapy of cancers that express appropriate nucleoside transporters and are sensitive to established nucleoside-derived cytostatic drugs.

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Inactivation of Non-canonical Cyclic Nucleotides: Hydrolysis and Transport

Schneider

Seifert

2016

Non-Canonical Cyclic Nucleotides

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This chapter addresses cNMP hydrolysis by phosphodiesterases (PDEs) and export by multidrug resistance associated proteins (MRPs). Both mechanisms are well-established for the canonical cNMPs, cAMP, and cGMP. Increasing evidence shows that non-canonical cNMPs (specifically cCMP, cUMP) are also PDE and MRP substrates. Hydrolysis of cUMP is achieved by PDE 3A, 3B, and 9A, which possibly explains the cUMP-degrading activities previously reported for heart, adipose tissue, and brain. Regarding cCMP, the only known "conventional" (class I) PDE that hydrolyzes cCMP is PDE7A. Older reports describe cCMP-degrading PDE-like activities in mammalian tissues, bacteria, and plants, but the molecular identity of these enzymes is not clear. High K and V values, insensitivity to common inhibitors, and unusually broad substrate specificities indicate that these activities probably do not represent class I PDEs. Moreover, the older results have to be interpreted with caution, since the historical analytical methods were not as reliable as modern highly sensitive and specific techniques like HPLC-MS/MS. Besides PDEs, the transporters MRP4 and 5 are of major importance for cAMP and cGMP disposal. Additionally, both MRPs also export cUMP, while cCMP is only exported by MRP5. Much less data are available for the non-canonical cNMPs, cIMP, cXMP, and cTMP. None of these cNMPs has been examined as MRP substrate. It was shown, however, that they are hydrolyzed by several conventional class I PDEs. Finally, this chapter reveals that there are still large gaps in our knowledge about PDE and MRP activities for canonical and non-canonical cNMPs. Future research should perform a comprehensive characterization of the known PDEs and MRPs with the physiologically most important cNMP substrates.

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cUMP hydrolysis by PDE3A

Cited by 7 publications

References 37 publications

Mechanistic insights into cancer cell killing through interaction of phosphodiesterase 3A and schlafen family member 12

Mechanistic insights into cancer cell killing through interaction of phosphodiesterase 3A and schlafen family member 12

Apoptotic and anti-proliferative effect of guanosine and guanosine derivatives in HuT-78 T lymphoma cells

Inactivation of Non-canonical Cyclic Nucleotides: Hydrolysis and Transport

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