The PKN1- TRAF1 signaling axis as a potential new target for chronic lymphocytic leukemia.
Chronic lymphocytic leukemia
TNFR-associated factors (TRAFS)
protein kinase N1
Journal
Oncoimmunology
ISSN: 2162-402X
Titre abrégé: Oncoimmunology
Pays: United States
ID NLM: 101570526
Informations de publication
Date de publication:
2021
2021
Historique:
entrez:
30
9
2021
pubmed:
1
10
2021
medline:
16
10
2021
Statut:
epublish
Résumé
TRAF1 is a pro-survival adaptor molecule in TNFR superfamily (TNFRSF) signaling. TRAF1 is overexpressed in many B cell cancers including refractory chronic lymphocytic leukemia (CLL). Little has been done to assess the role of TRAF1 in human cancer. Here we show that the protein kinase C related kinase Protein Kinase N1 (PKN1) is required to protect TRAF1 from cIAP-mediated degradation during constitutive CD40 signaling in lymphoma. We show that the active phospho-Thr774 form of PKN1 is constitutively expressed in CLL but minimally detected in unstimulated healthy donor B cells. Through a screen of 700 kinase inhibitors, we identified two inhibitors, OTSSP167, and XL-228, that inhibited PKN1 in the nanomolar range and induced dose-dependent loss of TRAF1 in RAJI cells. OTSSP167 or XL-228 treatment of primary patient CLL samples led to a reduction in TRAF1, pNF-κB p65, pS6, pERK, Mcl-1 and Bcl-2 proteins, and induction of activated caspase-3. OTSSP167 synergized with venetoclax in inducing CLL death, correlating with loss of TRAF1, Mcl-1, and Bcl-2. Although correlative, these findings suggest the PKN1-TRAF1 signaling axis as a potential new target for CLL. These findings also suggest the use of the orally available inhibitor OTSSP167 in combination treatment with venetoclax for TRAF1 overexpressing CLL.
Identifiants
pubmed: 34589290
doi: 10.1080/2162402X.2021.1943234
pii: 1943234
pmc: PMC8475556
doi:
Substances chimiques
1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone
0
Naphthyridines
0
Protein Kinase Inhibitors
0
TNF Receptor-Associated Factor 1
0
protein kinase N
EC 2.7.1.-
Protein Kinase C
EC 2.7.11.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1943234Subventions
Organisme : CIHR
ID : FDN-143250
Pays : Canada
Informations de copyright
© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.
Déclaration de conflit d'intérêts
No potential conflict of interest was reported by the author(s).
Références
Sci Rep. 2017 Aug 9;7(1):7663
pubmed: 28794483
N Engl J Med. 2015 Dec 17;373(25):2425-37
pubmed: 26639149
Blood. 2016 Nov 3;128(18):2193-2194
pubmed: 27811187
Blood. 2007 Dec 15;110(13):4455-63
pubmed: 17827388
Oncogene. 2018 Oct;37(41):5520-5533
pubmed: 29895969
Cancer Res. 2011 Feb 15;71(4):1385-95
pubmed: 21303981
Mol Immunol. 2009 Aug;46(13):2441-8
pubmed: 19540595
Immunol Rev. 2009 May;229(1):152-72
pubmed: 19426221
Bioorg Med Chem Lett. 2006 Apr 15;16(8):2173-6
pubmed: 16458503
Br J Haematol. 1999 Sep;106(4):995-1004
pubmed: 10520003
Blood. 2015 Jul 23;126(4):471-7
pubmed: 26065659
Nature. 2012 Sep 13;489(7415):309-12
pubmed: 22885698
N Engl J Med. 2016 Jan 28;374(4):311-22
pubmed: 26639348
Blood. 2011 Jan 13;117(2):563-74
pubmed: 20940416
Mol Cell. 2010 Apr 9;38(1):101-13
pubmed: 20385093
Leuk Lymphoma. 2017 Sep;58(9):1-17
pubmed: 28140720
Blood. 2007 Jul 15;110(2):743-51
pubmed: 17405906
Leuk Lymphoma. 2017 Feb;58(2):266-279
pubmed: 27756161
Nature. 2002 Mar 21;416(6878):345-7
pubmed: 11907583
Front Biosci (Elite Ed). 2010 Jan 01;2:241-9
pubmed: 20036874
J Immunol. 2000 Nov 1;165(9):5084-96
pubmed: 11046039
Oncotarget. 2014 Dec 30;5(24):12646-64
pubmed: 25504435
Science. 1996 Feb 2;271(5249):648-50
pubmed: 8571127
Lancet Oncol. 2016 Jun;17(6):768-778
pubmed: 27178240
J Exp Med. 1997 May 19;185(10):1777-83
pubmed: 9151703
Immunity. 1997 Nov;7(5):715-25
pubmed: 9390694
Hum Pathol. 2009 Oct;40(10):1434-40
pubmed: 19427017
J Immunol. 2006 May 1;176(9):5388-400
pubmed: 16622006
Blood Adv. 2017 Jun 13;1(14):933-946
pubmed: 29034364
Science. 1995 Sep 8;269(5229):1424-7
pubmed: 7544915
Cancer Discov. 2017 Oct;7(10):1069-1087
pubmed: 28923911
J Biol Chem. 2012 Jun 29;287(27):23010-9
pubmed: 22570473
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5089-94
pubmed: 10792047
Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9573-8
pubmed: 24979759
Oncotarget. 2012 Dec;3(12):1629-40
pubmed: 23283305
Nat Cell Biol. 2008 Jan;10(1):53-60
pubmed: 18066052
Oncogene. 2005 Nov 24;24(53):7913-23
pubmed: 16091748
Trends Biochem Sci. 2006 Jun;31(6):342-8
pubmed: 16679021
J Exp Med. 2002 Oct 7;196(7):923-34
pubmed: 12370254
Cell Signal. 2020 May;69:109546
pubmed: 31981797
Oncogene. 2002 Apr 11;21(16):2493-503
pubmed: 11971184
Immunity. 2001 Oct;15(4):647-57
pubmed: 11672546
Crit Rev Oncol Hematol. 2016 Apr;100:32-6
pubmed: 26899021
Genes Cells. 2008 May;13(5):509-20
pubmed: 18429822
Mol Cell. 2008 Jun 20;30(6):689-700
pubmed: 18570872
Br J Haematol. 2016 Aug;174(3):351-67
pubmed: 27291144
Front Immunol. 2018 Sep 20;9:2111
pubmed: 30294322
J Immunol. 2012 Jun 15;188(12):6071-83
pubmed: 22593611
Science. 2017 Dec 1;358(6367):
pubmed: 29191878
J Immunol. 2008 Jun 15;180(12):8093-101
pubmed: 18523273
Science. 1998 Sep 11;281(5383):1680-3
pubmed: 9733516
J Virol. 2003 Jan;77(2):1316-28
pubmed: 12502848
Front Immunol. 2018 Dec 18;9:2969
pubmed: 30619326
J Biol Chem. 2000 Apr 14;275(15):11064-70
pubmed: 10753910
Cell Death Differ. 2011 Aug;18(8):1376-86
pubmed: 21331077
Blood. 2016 Aug 18;128(7):934-47
pubmed: 27297795
Science. 1996 Feb 2;271(5249):645-8
pubmed: 8571126
Blood. 2018 Apr 12;131(15):1704-1711
pubmed: 29305552
PLoS Pathog. 2015 May 21;11(5):e1004890
pubmed: 25996949
J Immunol. 2002 Nov 1;169(9):4882-8
pubmed: 12391199
Future Med Chem. 2016 Sep;8(13):1537-51
pubmed: 27572962
J Immunol. 2018 Jan 15;200(2):558-564
pubmed: 29222166