Autophagy activation, lipotoxicity and lysosomal membrane permeabilization synergize to promote pimozide- and loperamide-induced glioma cell death.
Autophagy
/ drug effects
Autophagy-Related Protein 5
/ antagonists & inhibitors
Autophagy-Related Protein 7
/ antagonists & inhibitors
Brain Neoplasms
/ drug therapy
Cathepsins
/ metabolism
Cell Death
/ drug effects
Cell Line, Tumor
Ceramides
/ metabolism
Gene Knockout Techniques
Glioblastoma
/ drug therapy
Humans
Lipid Metabolism
/ drug effects
Loperamide
/ pharmacology
Lysosomes
/ drug effects
Permeability
/ drug effects
Pimozide
/ pharmacology
Proteome
/ metabolism
Sphingomyelin Phosphodiesterase
/ antagonists & inhibitors
Acid sphingomyelinase
autophagy-dependent cell death
brain tumors
cholesterol metabolism
drug repurposing
er stress
lysophagy
Journal
Autophagy
ISSN: 1554-8635
Titre abrégé: Autophagy
Pays: United States
ID NLM: 101265188
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
pubmed:
20
1
2021
medline:
25
3
2022
entrez:
19
1
2021
Statut:
ppublish
Résumé
Increasing evidence suggests that induction of lethal macroautophagy/autophagy carries potential significance for the treatment of glioblastoma (GBM). In continuation of previous work, we demonstrate that pimozide and loperamide trigger an ATG5- and ATG7 (autophagy related 5 and 7)-dependent type of cell death that is significantly reduced with cathepsin inhibitors and the lipid reactive oxygen species (ROS) scavenger α-tocopherol in MZ-54 GBM cells. Global proteomic analysis after treatment with both drugs also revealed an increase of proteins related to lipid and cholesterol metabolic processes. These changes were accompanied by a massive accumulation of cholesterol and other lipids in the lysosomal compartment, indicative of impaired lipid transport/degradation. In line with these observations, pimozide and loperamide treatment were associated with a pronounced increase of bioactive sphingolipids including ceramides, glucosylceramides and sphingoid bases measured by targeted lipidomic analysis. Furthermore, pimozide and loperamide inhibited the activity of SMPD1/ASM (sphingomyelin phosphodiesterase 1) and promoted induction of lysosomal membrane permeabilization (LMP), as well as release of CTSB (cathepsin B) into the cytosol in MZ-54 wild-type (WT) cells. Whereas LMP and cell death were significantly attenuated in
Identifiants
pubmed: 33461384
doi: 10.1080/15548627.2021.1874208
pmc: PMC8632287
doi:
Substances chimiques
ATG5 protein, human
0
Autophagy-Related Protein 5
0
Ceramides
0
Proteome
0
Pimozide
1HIZ4DL86F
Loperamide
6X9OC3H4II
SMPD1 protein, human
EC 3.1.4.12
Sphingomyelin Phosphodiesterase
EC 3.1.4.12
Cathepsins
EC 3.4.-
ATG7 protein, human
EC 6.2.1.45
Autophagy-Related Protein 7
EC 6.2.1.45
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3424-3443Références
Cancer Epidemiol Biomarkers Prev. 2014 Oct;23(10):1985-96
pubmed: 25053711
Int J Cancer. 2010 Jan 1;126(1):28-40
pubmed: 19662652
Cold Spring Harb Perspect Biol. 2011 Jun 01;3(6):
pubmed: 21502308
Mol Psychiatry. 2018 Dec;23(12):2324-2346
pubmed: 30038230
Front Pharmacol. 2018 Mar 16;9:218
pubmed: 29615902
Mol Pharmacol. 1994 Apr;45(4):747-57
pubmed: 8183255
Biochem Soc Trans. 2017 Dec 15;45(6):1323-1331
pubmed: 29150528
Oncotarget. 2017 Oct 23;8(61):104022-104036
pubmed: 29262618
Ann Transl Med. 2015 Dec;3(22):360
pubmed: 26807415
Crit Rev Oncol Hematol. 2018 Aug;128:96-109
pubmed: 29958636
Cancer Res. 2008 Aug 15;68(16):6623-33
pubmed: 18701486
Autophagy. 2018;14(10):1693-1709
pubmed: 29938581
Mol Cancer Res. 2010 Jul;8(7):1002-16
pubmed: 20587533
Autophagy. 2012 May 1;8(5):719-30
pubmed: 22647656
Cancer Cell. 2015 Oct 12;28(4):456-471
pubmed: 26412325
Nucleic Acids Res. 2016 Dec 15;44(22):11033
pubmed: 27683222
Nucleic Acids Res. 2015 Jan;43(Database issue):D447-52
pubmed: 25352553
Autophagy. 2016 Nov;12(11):2213-2229
pubmed: 27635674
Biochem Cell Biol. 2001;79(6):681-92
pubmed: 11800009
Pharmacogenomics J. 2010 Oct;10(5):396-407
pubmed: 19997082
PLoS One. 2011;6(8):e23852
pubmed: 21909365
J Biol Chem. 2004 Apr 30;279(18):18384-91
pubmed: 14970205
Oncogene. 2008 Oct 27;27(50):6434-51
pubmed: 18955971
Oncol Lett. 2016 Jan;11(1):575-583
pubmed: 26870250
PLoS One. 2016 Mar 31;11(3):e0152165
pubmed: 27031837
FEBS Lett. 2004 Feb 13;559(1-3):96-8
pubmed: 14960314
Biochim Biophys Acta. 2008 Nov-Dec;1781(11-12):724-30
pubmed: 18838129
EMBO J. 2013 Aug 28;32(17):2336-47
pubmed: 23921551
J Pharmacol Exp Ther. 1994 Jan;268(1):417-26
pubmed: 8301582
Cell Death Differ. 2017 Jul;24(7):1288-1302
pubmed: 28574511
Expert Opin Ther Targets. 2013 Mar;17(3):281-91
pubmed: 23293836
J Pineal Res. 2015 Sep;59(2):178-89
pubmed: 25975536
J Cell Sci. 2019 Feb 20;132(5):
pubmed: 30787029
EMBO J. 2017 Jan 17;36(2):135-150
pubmed: 27753622
Nat Rev Mol Cell Biol. 2014 Feb;15(2):81-94
pubmed: 24401948
EMBO J. 2001 Dec 3;20(23):6627-36
pubmed: 11726499
Ther Adv Med Oncol. 2016 Nov;8(6):421-428
pubmed: 27800031
Int J Mol Sci. 2018 Aug 01;19(8):
pubmed: 30071644
Oncogene. 2015 Oct 1;34(40):5105-13
pubmed: 25619832
Nat Protoc. 2008;3(6):1101-8
pubmed: 18546601
Metabolism. 2019 Jun;95:65-76
pubmed: 30954559
Autophagy. 2010 Nov;6(8):1057-65
pubmed: 20962572
J Crohns Colitis. 2016 Aug;10(8):965-78
pubmed: 26928964
J Med Chem. 2008 Jan 24;51(2):219-37
pubmed: 18027916
Nat Commun. 2017 Dec 4;8(1):1903
pubmed: 29199269
Cell Death Dis. 2018 Sep 24;9(10):994
pubmed: 30250198
Cell Death Dis. 2017 Mar 30;8(3):e2709
pubmed: 28358364
J Neurochem. 2003 Jan;84(2):273-81
pubmed: 12558990
Cell Death Differ. 2014 Jun;21(6):864-75
pubmed: 24488099
FEBS J. 2008 Apr;275(8):1925-36
pubmed: 18341587
Dev Cell. 2016 Oct 10;39(1):13-27
pubmed: 27693506
Sci Rep. 2018 Oct 5;8(1):14884
pubmed: 30291263
J Drug Target. 2011 Feb;19(2):125-32
pubmed: 20387992
Oncol Lett. 2016 Feb;11(2):1281-1286
pubmed: 26893731
J Cell Sci. 2018 Sep 20;131(18):
pubmed: 30237248
FEBS Lett. 2015 Nov 14;589(22):3343-53
pubmed: 26450776
Br J Cancer. 2017 Aug 8;117(4):513-524
pubmed: 28697173
Cold Spring Harb Perspect Biol. 2012 Jun 01;4(6):
pubmed: 22661635
Autophagy. 2007 Sep-Oct;3(5):413-6
pubmed: 17568180
J Clin Invest. 2002 May;109(9):1125-31
pubmed: 11994399
Cancer Cell. 2016 Nov 14;30(5):683-693
pubmed: 27746144
Cell Death Differ. 1999 Apr;6(4):370-6
pubmed: 10381630
J Clin Invest. 2009 May;119(5):1359-72
pubmed: 19425170
Ann N Y Acad Sci. 2016 May;1371(1):30-44
pubmed: 26599521
Nature. 2015 Aug 20;524(7565):361-5
pubmed: 26168401
J Proteome Res. 2014 Jun 6;13(6):3114-20
pubmed: 24766612
Nat Biotechnol. 1997 Sep;15(9):871-5
pubmed: 9306402
Clin J Oncol Nurs. 2016 Oct 1;20(5 Suppl):S2-8
pubmed: 27668386
Anticancer Agents Med Chem. 2010 Jul;10(6):438-49
pubmed: 20879985
Mol Cell. 2016 Nov 17;64(4):835-849
pubmed: 27818143
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
Biochem Biophys Rep. 2017 Mar 13;11:174-181
pubmed: 28955782
Nat Methods. 2016 Sep;13(9):731-40
pubmed: 27348712
Biology (Basel). 2019 Oct 29;8(4):
pubmed: 31671879
Cell Death Differ. 2018 Mar;25(3):486-541
pubmed: 29362479
Cancer Cell. 2013 Sep 9;24(3):379-93
pubmed: 24029234
Neuroscience. 2010 Apr 28;167(1):143-53
pubmed: 20123000
J Lipid Res. 2013 Feb;54(2):310-24
pubmed: 23175778
J Pharmacol Exp Ther. 1999 Apr;289(1):494-502
pubmed: 10087042
Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4764-9
pubmed: 20176935
Br J Pharmacol. 2010 Oct;161(3):481-7
pubmed: 20880389