Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
30 11 2020
30 11 2020
Historique:
received:
12
02
2020
accepted:
10
11
2020
revised:
07
11
2020
entrez:
1
12
2020
pubmed:
2
12
2020
medline:
28
4
2021
Statut:
epublish
Résumé
Colorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP. Due to the multiple molecular mechanisms-of-action of these targets, responses to IAP antagonist may differ between molecularly distinct colon cancer cells. In this study, responses to the IAP antagonist Birinapant and oxaliplatin/5-fluorouracil (5-FU) were investigated in 14 colon cancer cell lines, representing the consensus molecular subtypes (CMS). Treatment with Birinapant alone did not result in a substantial increase in apoptotic cells in this cell line panel. Annexin-V/PI assays quantified by flow cytometry and high-content screening showed that Birinapant increased responses of CMS1 and partially CMS3 cell lines to oxaliplatin/5-FU, whereas CMS2 cells were not effectively sensitized. FRET-based imaging of caspase-8 and -3 activation validated these differences at the single-cell level, with CMS1 cells displaying sustained activation of caspase-8-like activity during Birinapant and oxaliplatin/5-FU co-treatment, ultimately activating the intrinsic mitochondrial apoptosis pathway. In CMS2 cell lines, Birinapant exhibited synergistic effects in combination with TNFα, suggesting that Birinapant can restore extrinsic apoptosis signaling in the context of inflammatory signals in this subtype. To explore this further, we co-cultured CMS2 and CMS1 colon cancer cells with peripheral blood mononuclear cells. We observed increased cell death during Birinapant single treatment in these co-cultures, which was abrogated by anti-TNFα-neutralizing antibodies. Collectively, our study demonstrates that IAP inhibition is a promising modulator of response to oxaliplatin/5-FU in colorectal cancers of the CMS1 subtype, and may show promise as in the CMS2 subtype, suggesting that molecular subtyping may aid as a patient stratification tool for IAP antagonists in this disease.
Identifiants
pubmed: 33257690
doi: 10.1038/s41419-020-03232-z
pii: 10.1038/s41419-020-03232-z
pmc: PMC7705699
doi:
Substances chimiques
Dipeptides
0
Indoles
0
birinapant
6O4Z07B57R
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1020Subventions
Organisme : Cancer Research UK
ID : C11884/A24387
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 110371/Z/15/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S021205/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 24387
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/T002824/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400302
Pays : United Kingdom
Références
Surg Today. 2011 Feb;41(2):175-82
pubmed: 21264751
Curr Opin Immunol. 2017 Jun;46:14-22
pubmed: 28412583
Biochemistry. 2010 Sep 28;49(38):8307-15
pubmed: 20795673
Nat Commun. 2015 Apr 30;6:7002
pubmed: 25926053
J Surg Oncol. 2009 Dec 15;100(8):708-12
pubmed: 19777490
Apoptosis. 2010 Oct;15(10):1223-33
pubmed: 20563668
Nat Med. 2013 May;19(5):619-25
pubmed: 23584089
J Exp Med. 2010 Sep 27;207(10):2195-206
pubmed: 20837698
Cell Death Differ. 2017 Oct;24(10):1705-1716
pubmed: 28665401
J Immunother Cancer. 2016 Sep 20;4:51
pubmed: 27660705
Trends Cell Biol. 2019 Oct;29(10):777-790
pubmed: 31378317
Nat Rev Cancer. 2010 Aug;10(8):561-74
pubmed: 20651737
BMC Med Genomics. 2012 Dec 31;5:66
pubmed: 23272949
Nat Commun. 2017 Aug 24;8(1):344
pubmed: 28839138
JCO Precis Oncol. 2018 Jun 13;2018:
pubmed: 30088816
Cell Death Differ. 2018 Nov;25(11):1952-1966
pubmed: 29500433
PLoS Med. 2013;10(5):e1001453
pubmed: 23700391
Nat Med. 2015 Nov;21(11):1350-6
pubmed: 26457759
Nat Methods. 2010 Jun;7(6):418-9
pubmed: 20508634
Cell Death Differ. 2018 Mar;25(3):616-633
pubmed: 29305587
Int Biol Biomed J. 2017 Summer;3(3):105-111
pubmed: 28825047
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
Apoptosis. 2017 Jul;22(7):898-919
pubmed: 28424988
Gut. 2017 Dec;66(12):2141-2148
pubmed: 27663504
Eur J Immunol. 2007 Aug;37(8):2196-204
pubmed: 17595676
Oncotarget. 2017 Jun 13;8(24):39367-39381
pubmed: 28455965
J Biol Chem. 2008 Aug 1;283(31):21676-85
pubmed: 18522940
Cancers (Basel). 2019 Aug 14;11(8):
pubmed: 31416205
Blood. 2004 Oct 15;104(8):2418-24
pubmed: 15205263
Br J Cancer. 2016 Jan 19;114(2):188-98
pubmed: 26657652
PLoS Biol. 2008 Dec 2;6(12):2831-52
pubmed: 19053173
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Cell. 2016 Apr 21;165(3):631-42
pubmed: 27062928
BMC Cancer. 2016 Aug 12;16:624
pubmed: 27520705
Cell Death Dis. 2013 Sep 05;4:e784
pubmed: 24008728
Mol Syst Biol. 2015 May 07;11(5):803
pubmed: 25953765
Springerplus. 2016 Aug 11;5(1):1318
pubmed: 27563513
Cell Death Differ. 2008 Feb;15(2):322-31
pubmed: 17975551
Ann Oncol. 2019 Oct 1;30(10):1622-1629
pubmed: 31504112
Clin Cancer Res. 2015 Nov 15;21(22):5030-6
pubmed: 26567362
Nat Rev Cancer. 2017 Mar 23;17(4):268
pubmed: 28332502
J Clin Oncol. 2009 Jul 1;27(19):3109-16
pubmed: 19451431
Biochim Biophys Acta. 2008 Oct;1783(10):1903-13
pubmed: 18590777
Mol Cell. 2008 Jun 20;30(6):689-700
pubmed: 18570872
Nat Rev Immunol. 2015 Aug;15(8):486-99
pubmed: 26205583
JAMA Oncol. 2016 Sep 1;2(9):1162-9
pubmed: 27270348
Sci Adv. 2019 Jul 31;5(7):eaau9433
pubmed: 31392262
Gut. 2012 May;61(5):725-33
pubmed: 22082587
Clin Cancer Res. 2005 Aug 1;11(15):5451-61
pubmed: 16061861
Nature. 2012 Jul 18;487(7407):330-7
pubmed: 22810696
Biochim Biophys Acta. 2009 Apr;1795(2):117-29
pubmed: 19167459
Arch Pharm Res. 2019 Jul;42(7):567-581
pubmed: 30843144
Biochim Biophys Acta. 2012 Oct;1823(10):1825-40
pubmed: 22801217
Clin Cancer Res. 2017 Mar 1;23(5):1200-1212
pubmed: 27649552
Mol Cancer Ther. 2014 Apr;13(4):867-79
pubmed: 24563541
Breast Cancer Res Treat. 2013 Jan;137(2):359-71
pubmed: 23225169
Clin Cancer Res. 2012 Dec 1;18(23):6531-41
pubmed: 23045248
CA Cancer J Clin. 2018 Nov;68(6):394-424
pubmed: 30207593
Nat Commun. 2018 Jan 26;9(1):389
pubmed: 29374163
J Immunol. 1999 Feb 15;162(4):1889-95
pubmed: 9973455
Surg Oncol. 2019 Sep;30:100-107
pubmed: 31500770