Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells.
Gene expression analysis
Haematological cancer
Molecular biology
Molecular medicine
Journal
Signal transduction and targeted therapy
ISSN: 2059-3635
Titre abrégé: Signal Transduct Target Ther
Pays: England
ID NLM: 101676423
Informations de publication
Date de publication:
Historique:
received:
12
11
2018
revised:
05
02
2019
accepted:
04
04
2019
entrez:
27
6
2019
pubmed:
27
6
2019
medline:
27
6
2019
Statut:
epublish
Résumé
The phosphatidylinositol 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) pathway is constitutively activated in human acute myeloid leukemia (AML) cells and is regarded as a possible therapeutic target. Insulin is an agonist of this pathway and a growth factor for AML cells. We characterized the effect of insulin on the phosphorylation of 10 mediators in the main track of the PI3K-Akt-mTOR pathway in AML cells from 76 consecutive patients. The overall results showed that insulin significantly increased the phosphorylation of all investigated mediators. However, insulin effects on the pathway activation profile varied among patients, and increased phosphorylation in all mediators was observed only in a minority of patients; in other patients, insulin had divergent effects. Global gene expression profiling and proteomic/phosphoproteomic comparisons suggested that AML cells from these two patient subsets differed with regard to AML cell differentiation, transcriptional regulation, RNA metabolism, and cellular metabolism. Strong insulin-induced phosphorylation was associated with weakened antiproliferative effects of metabolic inhibitors. PI3K, Akt, and mTOR inhibitors also caused divergent effects on the overall pathway phosphorylation profile in the presence of insulin, although PI3K and Akt inhibition caused a general reduction in Akt pT308 and 4EBP1 pT36/pT45 phosphorylation. For Akt inhibition, the phosphorylation of upstream mediators was generally increased or unaltered. In contrast, mTOR inhibition reduced mTOR pS2448 and S6 pS244 phosphorylation but increased Akt pT308 phosphorylation. In conclusion, the effects of both insulin and PI3K-Akt-mTOR inhibitors differ between AML patient subsets, and differences in insulin responsiveness are associated with differential susceptibility to metabolic targeting.
Identifiants
pubmed: 31240133
doi: 10.1038/s41392-019-0050-0
pii: 50
pmc: PMC6582141
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
20Déclaration de conflit d'intérêts
Competing interestsThe authors declare no competing interests.
Références
Eur J Haematol. 1999 Mar;62(3):191-8
pubmed: 10089897
Stem Cells. 2001;19(1):1-11
pubmed: 11209086
J Hematother Stem Cell Res. 2002 Jun;11(3):469-81
pubmed: 12183832
Haematologica. 2003 Apr;88(4):416-28
pubmed: 12681969
Transfusion. 2005 Apr;45(4):622-33
pubmed: 15819685
Leuk Res. 2006 Dec;30(12):1531-40
pubmed: 16600371
Leukemia. 2007 Sep;21(9):1921-30
pubmed: 17581609
Blood. 2008 Jan 1;111(1):379-82
pubmed: 17878402
Semin Cancer Biol. 2009 Feb;19(1):25-31
pubmed: 19130886
Nat Methods. 2009 May;6(5):359-62
pubmed: 19377485
Expert Opin Investig Drugs. 2009 Sep;18(9):1333-49
pubmed: 19678801
Oncotarget. 2010 Jun;1(2):89-103
pubmed: 20671809
J Proteome Res. 2011 Feb 4;10(2):913-20
pubmed: 21067241
Nat Med. 2011 Aug 28;17(9):1086-93
pubmed: 21873988
Br J Haematol. 2012 Feb;156(4):468-80
pubmed: 22150087
Blood. 2012 Sep 20;120(12):2466-74
pubmed: 22786882
J Mol Endocrinol. 2013 Apr 23;50(3):R67-74
pubmed: 23493758
Invest New Drugs. 2013 Dec;31(6):1505-13
pubmed: 23982248
Oncotarget. 2013 Sep;4(9):1438-48
pubmed: 23988457
Br J Haematol. 2014 Jan;164(2):200-11
pubmed: 24383842
Endocr Connect. 2014 Jan 28;3(1):24-35
pubmed: 24434591
Protein Cell. 2014 Mar;5(3):203-13
pubmed: 24633815
Br J Haematol. 2014 Aug;166(3):401-9
pubmed: 24761838
Methods Enzymol. 2014;542:59-80
pubmed: 24862260
Am J Physiol Renal Physiol. 2014 Aug 15;307(4):F435-44
pubmed: 24990892
Blood. 2014 Sep 4;124(10):1645-54
pubmed: 25006128
Leuk Lymphoma. 2015;56(11):3135-42
pubmed: 25735964
Eur J Haematol. 2016 Mar;96(3):211-21
pubmed: 26465810
J Exp Med. 2015 Dec 14;212(13):2305-21
pubmed: 26573296
J Proteomics. 2016 Aug 11;145:214-225
pubmed: 27107777
PLoS One. 2016 May 05;11(5):e0154415
pubmed: 27149630
Biol Proced Online. 2016 Jun 21;18:13
pubmed: 27330413
Recent Results Cancer Res. 2016;207:39-72
pubmed: 27557534
Molecules. 2016 Nov 11;21(11):
pubmed: 27845732
Blood. 2017 Jan 26;129(4):424-447
pubmed: 27895058
Proteomes. 2016 Aug 22;4(3):
pubmed: 28248234
Expert Opin Ther Targets. 2017 Apr;21(4):357-369
pubmed: 28281897
Expert Opin Drug Discov. 2017 Oct;12(10):1053-1065
pubmed: 28748730
BMC Cancer. 2017 Sep 6;17(1):630
pubmed: 28877686
Int J Mol Sci. 2018 Jan 27;19(2):null
pubmed: 29382066
J Mol Endocrinol. 2018 Jul;61(1):T69-T86
pubmed: 29535161
Expert Opin Investig Drugs. 2018 Apr;27(4):377-387
pubmed: 29611449
J Bioenerg Biomembr. 2018 Aug;50(4):271-281
pubmed: 29882205
Expert Opin Ther Targets. 2018 Jul;22(7):639-653
pubmed: 29889583
Front Pharmacol. 2018 Jun 29;9:687
pubmed: 30013477
Leuk Res. 1988;12(2):157-65
pubmed: 3162753
Leuk Res. 1995 Apr;19(4):233-40
pubmed: 7538616
Scand J Immunol. 1993 Jul;38(1):65-74
pubmed: 8327861