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

Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE

Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology

Cyclic Nucleotide Phosphodiesterases, Type 3/*metabolism ; Intracellular Signaling Peptides and Proteins/*metabolism ; Neoplasms/*pathology; Base Sequence ; Biomarkers, Tumor/metabolism ; CRISPR-Cas Systems/genetics ; Catalytic Domain ; Cell Death/drug effects ; Cell Line, Tumor ; Cyclic Nucleotide Phosphodiesterases, Type 3/chemistry ; Frameshift Mutation/genetics ; Genome ; Heterozygote ; Humans ; Protein Binding/drug effects ; Pyridazines/pharmacology

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(2 H )-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.
(© 2020 Wu et al.)

Erratum in: J Biol Chem. 2020 Nov 27;295(48):16464-16467. (PMID: 33246941)

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R35 CA197568 United States CA NCI NIH HHS

Keywords: AIP; DNMDP; PDE3A; PDE3B; SLFN12; biomarker; cancer biology; cancer therapy; cell death; chaperone; phosphodiesterases; protein-protein interaction

0 (6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one)
0 (Biomarkers, Tumor)
0 (Intracellular Signaling Peptides and Proteins)
0 (Pyridazines)
0 (SLFN12 protein, human)
0 (aryl hydrocarbon receptor-interacting protein)
EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)

Date Created: 20200202 Date Completed: 20201207 Latest Revision: 20210329

20240829

PMC7076209

10.1074/jbc.RA119.011191

32005668