Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
27 02 2023
27 02 2023
Historique:
received:
14
09
2022
accepted:
15
02
2023
revised:
14
02
2023
entrez:
27
2
2023
pubmed:
28
2
2023
medline:
3
3
2023
Statut:
epublish
Résumé
Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have yet to be established. We previously reported that a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, ZSTK474, was effective for the treatment of sarcomas in a phase I clinical trial. We also demonstrated the efficacy of ZSTK474 in a preclinical model, particularly in cell lines from synovial sarcoma (SS), Ewing's sarcoma (ES) and alveolar rhabdomyosarcoma (ARMS), all of which harbor chromosomal translocations. ZSTK474 selectively induced apoptosis in all these sarcoma cell lines, although the precise mechanism underlying the induction of apoptosis remained unclear. In the present study, we aimed to determine the antitumor effect of PI3K inhibitors, particularly with regards to the induction of apoptosis, against various TRS subtypes using cell lines and patient-derived cells (PDCs). All of the cell lines derived from SS (six), ES (two) and ARMS (one) underwent apoptosis accompanied by the cleavage of poly-(ADP-ribose) polymerase (PARP) and the loss of mitochondrial membrane potential. We also observed apoptotic progression in PDCs from SS, ES and clear cell sarcoma (CCS). Transcriptional analyses revealed that PI3K inhibitors triggered the induction of PUMA and BIM and the knockdown of these genes by RNA interference efficiently suppressed apoptosis, suggesting their functional involvement in the progression of apoptosis. In contrast, TRS-derived cell lines/PDCs from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. Thus, we conclude that PI3K inhibitors induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and the subsequent loss of mitochondrial membrane potential. This represents proof of concept for PI3K-targeted therapy, particularly such TRS patients.
Identifiants
pubmed: 36849535
doi: 10.1038/s41419-023-05690-7
pii: 10.1038/s41419-023-05690-7
pmc: PMC9971170
doi:
Substances chimiques
Apoptosis Regulatory Proteins
0
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
Phosphoinositide-3 Kinase Inhibitors
0
BBC3 protein, human
0
Bcl-2-Like Protein 11
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
169Informations de copyright
© 2023. The Author(s).
Références
Nat Cell Biol. 2002 Nov;4(11):842-9
pubmed: 12402042
Nat Rev Cancer. 2009 Aug;9(8):550-62
pubmed: 19629070
Cancer Genet Cytogenet. 2003 Mar;141(2):138-42
pubmed: 12606131
Hum Cell. 2018 Apr;31(2):167-174
pubmed: 29450702
Mol Cell Biol. 1993 Dec;13(12):7393-8
pubmed: 8246959
Histopathology. 2021 Apr;78(5):644-657
pubmed: 33438273
Cancer Genet Cytogenet. 2009 Apr 15;190(2):75-80
pubmed: 19380023
Nat Rev Mol Cell Biol. 2020 Feb;21(2):85-100
pubmed: 31636403
Clin Cancer Res. 2009 Feb 1;15(3):1096-104
pubmed: 19188185
Mol Cancer Ther. 2011 Jun;10(6):1018-27
pubmed: 21490307
Biochem Biophys Res Commun. 2009 Jan 30;379(1):104-9
pubmed: 19094964
Cancer Discov. 2015 May;5(5):475-87
pubmed: 25895919
Eur J Cancer. 2012 Apr;48(6):936-43
pubmed: 22088482
Stem Cells. 2010 Jul;28(7):1119-31
pubmed: 20518020
Ann Oncol. 2019 Dec;30 Suppl 10:x12-x20
pubmed: 31928690
Nat Rev Cancer. 2015 Jan;15(1):7-24
pubmed: 25533673
Science. 1976 Nov 26;194(4268):951-3
pubmed: 62397
In Vitro Cell Dev Biol Anim. 2018 Feb;54(2):163-176
pubmed: 29197033
Hum Cell. 2020 Oct;33(4):1302-1310
pubmed: 32648033
Nat Rev Cancer. 2018 Mar;18(3):148-167
pubmed: 29348577
Mol Cell. 2001 Mar;7(3):673-82
pubmed: 11463391
Cancer. 1969 Sep;24(3):520-6
pubmed: 4241949
Cancer Res. 2005 May 1;65(9):3868-76
pubmed: 15867386
Cancer Discov. 2019 Apr;9(4):482-491
pubmed: 30867161
PLoS One. 2017 Apr 5;12(4):e0174905
pubmed: 28380010
Acta Pathol Jpn. 1990 Jul;40(7):486-93
pubmed: 2171298
Cancer Res. 2002 Jul 1;62(13):3861-7
pubmed: 12097301
Cancer. 1971 Feb;27(2):397-402
pubmed: 5100401
J Pediatr Hematol Oncol. 2011 Jul;33(5):360-8
pubmed: 21552147
Cancer Lett. 2004 Feb 10;204(1):105-13
pubmed: 14744540
Oncogene. 2007 Feb 26;26(9):1324-37
pubmed: 17322918
In Vitro Cell Dev Biol Anim. 2019 Jan;55(1):62-73
pubmed: 30411273
Nat Rev Cancer. 2011 Jul 14;11(8):541-57
pubmed: 21753790
J Lipid Res. 2019 Apr;60(4):747-752
pubmed: 30718284
J Pathol. 2008 Dec;216(4):428-39
pubmed: 18855347
Cancer Res. 2007 Dec 15;67(24):11867-75
pubmed: 18089817
Oncotarget. 2018 Oct 12;9(80):35141-35161
pubmed: 30416685
Cell Death Differ. 2018 Jan;25(1):65-80
pubmed: 29149100
Exp Cell Res. 2000 May 1;256(2):375-82
pubmed: 10772810
J Natl Cancer Inst. 1977 Jul;59(1):221-6
pubmed: 327080
Mol Cell Biol. 1995 Mar;15(3):1522-35
pubmed: 7862145
Clin Cancer Res. 2007 Aug 15;13(16):4934-42
pubmed: 17652623
Curr Treat Options Oncol. 2019 Jan 24;20(1):6
pubmed: 30675651
Cancer Sci. 2012 Nov;103(11):1955-60
pubmed: 22925034
Cell Death Dis. 2020 Nov 2;11(11):943
pubmed: 33139695
Trends Endocrinol Metab. 2005 May-Jun;16(4):183-9
pubmed: 15860415
Cell Death Dis. 2018 Sep 17;9(10):935
pubmed: 30224718
Clin Cancer Res. 2019 Jun 15;25(12):3718-3731
pubmed: 30814111
JAMA Oncol. 2019 Feb 1;5(2):254-260
pubmed: 30347044
In Vitro Cell Dev Biol Anim. 2018 Dec;54(10):770-778
pubmed: 30324244
J Clin Invest. 1994 Aug;94(2):489-96
pubmed: 8040301
J Natl Cancer Inst. 2006 Apr 19;98(8):545-56
pubmed: 16622124
Nat Rev Clin Oncol. 2018 May;15(5):273-291
pubmed: 29508857
Int J Mol Sci. 2018 Nov 28;19(12):
pubmed: 30487384
Hum Cell. 2020 Apr;33(2):427-436
pubmed: 31898195
Int J Mol Sci. 2018 Mar 05;19(3):
pubmed: 29510588
Biomed Pharmacother. 2018 Jul;103:889-896
pubmed: 29710505
J Clin Invest. 2014 Jul;124(7):3061-74
pubmed: 24911143
Cancer Lett. 2003 Jan 28;189(2):221-30
pubmed: 12490315
Mol Cell. 2001 Mar;7(3):683-94
pubmed: 11463392
Science. 2003 Nov 7;302(5647):1036-8
pubmed: 14500851
J Pathol. 2009 Mar;217(4):469-82
pubmed: 19148905
Curr Treat Options Oncol. 2018 Oct 25;19(12):65
pubmed: 30361919
Nat Genet. 1994 Aug;7(4):502-8
pubmed: 7951320
Cell Death Differ. 2018 Jan;25(1):46-55
pubmed: 29053143
Clin Cancer Res. 2005 Apr 1;11(7):2702-12
pubmed: 15814652
Cancer Res. 1993 Aug 15;53(16):3655-7
pubmed: 8339272
J Natl Cancer Inst. 1977 Feb;58(2):209-14
pubmed: 833871