Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells.
Amides
/ pharmacology
Apoptosis
/ drug effects
Cell Survival
/ drug effects
Ceramidases
/ metabolism
Ceramides
/ metabolism
Fatty Acids, Unsaturated
/ pharmacology
Glucosyltransferases
/ metabolism
HL-60 Cells
Humans
Immunoblotting
Lysophospholipids
/ metabolism
Mass Spectrometry
Mitochondria
/ metabolism
Reverse Transcriptase Polymerase Chain Reaction
Sphingolipids
/ metabolism
Sphingosine
/ analogs & derivatives
cancer
ceramide
drug resistance
sphingolipids
Journal
Journal of lipid research
ISSN: 1539-7262
Titre abrégé: J Lipid Res
Pays: United States
ID NLM: 0376606
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
08
07
2019
revised:
27
07
2019
pubmed:
1
8
2019
medline:
21
7
2020
entrez:
1
8
2019
Statut:
ppublish
Résumé
The combination of daunorubicin (dnr) and cytarabine (Ara-C) is a cornerstone of treatment for acute myelogenous leukemia (AML); resistance to these drugs is a major cause of treatment failure. Ceramide, a sphingolipid (SL), plays a critical role in cancer cell apoptosis in response to chemotherapy. Here, we investigated the effects of chemotherapy selection pressure with Ara-C and dnr on SL composition and enzyme activity in the AML cell line HL-60. Resistant cells, those selected for growth in Ara-C- and dnr-containing medium (HL-60/Ara-C and HL-60/dnr, respectively), demonstrated upregulated expression and activity of glucosylceramide synthase, acid ceramidase (AC), and sphingosine kinase 1 (SPHK1); were more resistant to ceramide than parental cells; and displayed sensitivity to inhibitors of SL metabolism. Lipidomic analysis revealed a general ceramide deficit and a profound upswing in levels of sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) in HL-60/dnr cells versus parental and HL-60/Ara-C cells. Both chemotherapy-selected cells also exhibited comprehensive upregulations in mitochondrial biogenesis consistent with heightened reliance on oxidative phosphorylation, a property that was partially reversed by exposure to AC and SPHK1 inhibitors and that supports a role for the phosphorylation system in resistance. In summary, dnr and Ara-C selection pressure induces acute reductions in ceramide levels and large increases in S1P and C1P, concomitant with cell resilience bolstered by enhanced mitochondrial remodeling. Thus, strategic control of ceramide metabolism and further research to define mitochondrial perturbations that accompany the drug-resistant phenotype offer new opportunities for developing therapies that regulate cancer growth.
Identifiants
pubmed: 31363040
pii: S0022-2275(20)32320-8
doi: 10.1194/jlr.RA119000251
pmc: PMC6718434
pii:
doi:
Substances chimiques
(2R,3Z)-N-(1-hydroxyoctadec-3-en-2-yl)pivalamide
0
Amides
0
Ceramides
0
Fatty Acids, Unsaturated
0
Lysophospholipids
0
Sphingolipids
0
ceramide 1-phosphate
0
sphingosine 1-phosphate
26993-30-6
Glucosyltransferases
EC 2.4.1.-
ceramide glucosyltransferase
EC 2.4.1.80
Ceramidases
EC 3.5.1.23
Sphingosine
NGZ37HRE42
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1590-1602Subventions
Organisme : NCI NIH HHS
ID : P01 CA171983
Pays : United States
Informations de copyright
Copyright © 2019 Kao et al.
Références
J Cell Biol. 1999 Nov 1;147(3):545-58
pubmed: 10545499
Leukemia. 2000 Mar;14(3):467-73
pubmed: 10720143
J Natl Cancer Inst. 2001 Mar 7;93(5):347-57
pubmed: 11238696
FASEB J. 2001 Mar;15(3):719-30
pubmed: 11259390
Br J Haematol. 2002 Jun;117(4):860-8
pubmed: 12060121
FASEB J. 2002 Oct;16(12):1685-7
pubmed: 12206990
Biochim Biophys Acta. 2002 Oct 10;1584(2-3):99-103
pubmed: 12385892
Clin Cancer Res. 2003 Jan;9(1):415-23
pubmed: 12538495
Can J Biochem Physiol. 1959 Aug;37(8):911-7
pubmed: 13671378
Leukemia. 2006 Jan;20(1):95-102
pubmed: 16281067
Biochim Biophys Acta. 2006 Dec;1758(12):1864-84
pubmed: 17052686
Chembiochem. 2007 Apr 16;8(6):642-8
pubmed: 17361980
Nat Protoc. 2006;1(3):1559-82
pubmed: 17406449
Expert Opin Drug Metab Toxicol. 2007 Jun;3(3):363-77
pubmed: 17539744
Leuk Res. 2008 Mar;32(3):475-80
pubmed: 17709137
J Clin Invest. 2007 Sep;117(9):2408-21
pubmed: 17717597
Cancer Biol Ther. 2007 Sep;6(9):1455-60
pubmed: 17881906
Blood. 2008 Aug 15;112(4):1382-91
pubmed: 18511810
Nat Protoc. 2008;3(6):1101-8
pubmed: 18546601
Ann Intern Med. 1991 Dec 15;115(12):931-5
pubmed: 1952489
J Lipid Res. 2010 Apr;51(4):866-74
pubmed: 19826105
Mol Cancer. 2010 Feb 09;9:33
pubmed: 20144215
Biochimie. 2010 Jun;92(6):716-23
pubmed: 20167244
Future Oncol. 2010 Oct;6(10):1603-24
pubmed: 21062159
Cancer Biol Ther. 2011 Jan 15;11(2):138-49
pubmed: 21209555
Int J Oncol. 2011 Apr;38(4):911-9
pubmed: 21290089
J Biol Chem. 2011 May 27;286(21):18633-40
pubmed: 21464128
Prostate. 2011 Jul;71(10):1064-73
pubmed: 21557271
Anticancer Agents Med Chem. 2011 Nov;11(9):891-903
pubmed: 21707483
Drug Resist Updat. 2012 Feb-Apr;15(1-2):62-9
pubmed: 22409994
Exp Oncol. 2012 Oct;34(3):231-42
pubmed: 23070008
Nat Rev Cancer. 2013 Jan;13(1):51-65
pubmed: 23235911
Exp Hematol. 2013 Jul;41(7):597-603.e2
pubmed: 23507523
Handb Exp Pharmacol. 2013;(216):3-27
pubmed: 23563649
Handb Exp Pharmacol. 2013;(216):73-91
pubmed: 23563652
Handb Exp Pharmacol. 2013;(215):153-66
pubmed: 23579454
J Biol Chem. 1990 Sep 5;265(25):14917-21
pubmed: 2394706
J Clin Invest. 2013 Oct;123(10):4344-58
pubmed: 24091326
Methods Enzymol. 2013;533:235-40
pubmed: 24182928
Int J Mol Sci. 2014 Mar 12;15(3):4356-92
pubmed: 24625663
Glycoconj J. 2014 Oct;31(6-7):449-59
pubmed: 25129488
Int J Mol Sci. 2015 Jan 02;16(1):924-49
pubmed: 25561239
J Pharmacol Exp Ther. 2015 Mar;352(3):494-508
pubmed: 25563902
Adv Cancer Res. 2015;125:171-96
pubmed: 25640270
Apoptosis. 2015 May;20(5):689-711
pubmed: 25702155
Biol Chem. 2015 Jun;396(6-7):669-79
pubmed: 25719313
Pediatr Blood Cancer. 2016 Feb;63(2):242-7
pubmed: 26512967
Annu Rev Pharmacol Toxicol. 2016;56:85-102
pubmed: 26514196
PLoS One. 2016 Jan 19;11(1):e0146618
pubmed: 26783755
Med Sci Sports Exerc. 2016 Jun;48(6):990-1000
pubmed: 26807634
J Lipid Res. 2016 Jul;57(7):1231-42
pubmed: 27140664
Oncotarget. 2016 Dec 13;7(50):83208-83222
pubmed: 27825124
Blood. 2017 Feb 9;129(6):771-782
pubmed: 27956387
Biochem Pharmacol. 2017 Apr 15;130:21-33
pubmed: 28189725
Cancer Discov. 2017 Jul;7(7):716-735
pubmed: 28416471
Cell Signal. 2017 Oct;38:134-145
pubmed: 28687494
Cancer Transl Med. 2017 Jul-Aug;3(4):109-121
pubmed: 28890935
Adv Biol Regul. 2018 May;68:97-106
pubmed: 28942351
Nat Rev Cancer. 2018 Jan;18(1):33-50
pubmed: 29147025
Best Pract Res Clin Haematol. 2017 Dec;30(4):301-305
pubmed: 29156199
Br J Haematol. 2018 Apr;181(1):27-37
pubmed: 29318584
Adv Cancer Res. 2018;140:217-234
pubmed: 30060810
Adv Cancer Res. 2018;140:235-263
pubmed: 30060811
J Lipid Res. 2019 Apr;60(4):819-831
pubmed: 30573560
Cell. 1995 Aug 11;82(3):405-14
pubmed: 7634330
EMBO J. 1996 May 15;15(10):2417-24
pubmed: 8665849
Anticancer Res. 1996 Mar-Apr;16(2):709-14
pubmed: 8687117
Biochem Mol Biol Int. 1996 Nov;40(4):709-19
pubmed: 8950029
J Biol Chem. 1999 Jan 8;274(2):1140-6
pubmed: 9873062