The cytotoxic action of BCI is not dependent on its stated DUSP1 or DUSP6 targets in neuroblastoma cells.
CRISPR-Cas9
MAPK signalling
chemical inhibition
dual-specificity phosphatase
neuroblastoma
phosphoproteomics
Journal
FEBS open bio
ISSN: 2211-5463
Titre abrégé: FEBS Open Bio
Pays: England
ID NLM: 101580716
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
04
04
2022
received:
21
12
2021
accepted:
26
04
2022
pubmed:
29
4
2022
medline:
8
7
2022
entrez:
28
4
2022
Statut:
ppublish
Résumé
Neuroblastoma (NB) is a heterogeneous cancer of the sympathetic nervous system, which accounts for 7-10% of paediatric malignancies worldwide. Due to the lack of targetable molecular aberrations in NB, most treatment options remain relatively nonspecific. Here, we investigated the therapeutic potential of BCI, an inhibitor of DUSP1 and DUSP6, in cultured NB cells. BCI was cytotoxic in a range of NB cell lines and induced a short-lived activation of the AKT and stress-inducible MAP kinases, although ERK phosphorylation was unaffected. Furthermore, a phosphoproteomic screen identified significant upregulation of JNK signalling components and suppression in mTOR and R6K signalling. To assess the specificity of BCI, CRISPR-Cas9 was employed to introduce insertions and deletions in the DUSP1 and DUSP6 genes. Surprisingly, BCI remained fully cytotoxic in NB cells with complete loss of DUSP6 and partial depletion of DUSP1, suggesting that BCI exerts cytotoxicity in NB cells through a complex mechanism that is unrelated to these phosphatases. Overall, these data highlight the risk of using an inhibitor such as BCI as supposedly specific DUSP1/6, without understanding its full range of targets in cancer cells.
Identifiants
pubmed: 35478300
doi: 10.1002/2211-5463.13418
pmc: PMC9249316
doi:
Substances chimiques
Antineoplastic Agents
0
DUSP1 protein, human
EC 3.1.3.48
DUSP6 protein, human
EC 3.1.3.48
Dual Specificity Phosphatase 1
EC 3.1.3.48
Dual Specificity Phosphatase 6
EC 3.1.3.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1388-1405Subventions
Organisme : Blood Cancer UK
ID : 20008
Pays : United Kingdom
Informations de copyright
© 2022 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Références
Clin Cancer Res. 2019 Jul 1;25(13):4117-4127
pubmed: 30936125
Biochem Pharmacol. 2014 Mar 15;88(2):201-15
pubmed: 24468133
Neurosci Lett. 2019 Mar 23;696:60-66
pubmed: 30552945
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
J Med Chem. 2020 Oct 22;63(20):11368-11396
pubmed: 32460492
Cell Chem Biol. 2017 Nov 16;24(11):1388-1400.e7
pubmed: 28965727
Cell Biosci. 2012 Jul 09;2(1):24
pubmed: 22769588
Chembiochem. 2014 Jul 7;15(10):1436-45
pubmed: 24909879
Oncogene. 2008 May 1;27(20):2910-22
pubmed: 18026138
Nat Chem Biol. 2009 Sep;5(9):680-7
pubmed: 19578332
Cell Tissue Res. 2018 May;372(2):195-209
pubmed: 29572647
Cancer Lett. 2018 Jan 1;412:243-255
pubmed: 29050982
Cancer Metastasis Rev. 2008 Jun;27(2):253-61
pubmed: 18330678
Proteomics. 2015 Aug;15(15):2597-601
pubmed: 25921073
Oncogene. 2018 Mar;37(11):1417-1429
pubmed: 29321660
Biochemistry. 2006 Jul 18;45(28):8476-87
pubmed: 16834321
J Proteome Res. 2019 Feb 1;18(2):623-632
pubmed: 30450911
Int J Mol Sci. 2019 Mar 07;20(5):
pubmed: 30866462
Future Med Chem. 2010 Oct;2(10):1563-76
pubmed: 21426149
J Clin Oncol. 2015 Sep 20;33(27):3008-17
pubmed: 26304901
Sci Transl Med. 2019 Sep 11;11(509):
pubmed: 31511426
Mol Cancer Ther. 2009 Aug;8(8):2461-9
pubmed: 19671766
Nat Biotechnol. 2020 Apr;38(4):493-502
pubmed: 31959955
Sci Signal. 2013 Mar 26;6(268):rs6
pubmed: 23532336
Immune Netw. 2016 Apr;16(2):85-98
pubmed: 27162525
Oncotarget. 2017 Apr 4;8(14):23760-23774
pubmed: 28423600
J Immunol Res. 2018 Jul 11;2018:7394268
pubmed: 30116755
J Biomol Screen. 2015 Jun;20(5):663-72
pubmed: 25477201
Mol Cell Proteomics. 2012 Aug;11(8):453-66
pubmed: 22547687
Am J Physiol Cell Physiol. 2010 Aug;299(2):C189-202
pubmed: 20463170
Nature. 2003 Jun 12;423(6941):769-73
pubmed: 12802338
Nat Rev Cancer. 2003 Mar;3(3):203-16
pubmed: 12612655
Front Pharmacol. 2021 Nov 01;12:772540
pubmed: 34803714
Genes Cells. 2021 Feb;26(2):109-116
pubmed: 33249692
Cell. 2005 Mar 11;120(5):649-61
pubmed: 15766528
Cancer Cell. 2015 Jul 13;28(1):114-28
pubmed: 26073130
J Pharmacol Exp Ther. 2017 Apr;361(1):39-50
pubmed: 28154014
Sci Adv. 2020 Mar 25;6(13):eaaz0361
pubmed: 32232156
Biochim Biophys Acta Mol Cell Res. 2019 Jan;1866(1):124-143
pubmed: 30401534
Methods. 2011 Aug;54(4):370-8
pubmed: 21316455
Brain Res. 2012 Feb 3;1436:137-46
pubmed: 22197701
Oncotarget. 2019 May 21;10(36):3315-3327
pubmed: 31164954
Sci Data. 2017 Mar 28;4:170033
pubmed: 28350380
FEBS Open Bio. 2018 Aug 01;8(9):1405-1411
pubmed: 30186742
F1000Res. 2020 Feb 28;9:157
pubmed: 32399202
Nucleic Acids Res. 2020 Jul 2;48(W1):W488-W493
pubmed: 32246720
PLoS One. 2020 Oct 2;15(10):e0240044
pubmed: 33007022
J Biol Chem. 2006 Dec 15;281(50):38834-44
pubmed: 17046812
BMC Genomics. 2015;16 Suppl 8:S1
pubmed: 26110438
Pediatr Blood Cancer. 2013 Jun;60(6):985-93
pubmed: 23255319
Mol Cell Proteomics. 2005 Jul;4(7):873-86
pubmed: 15858219