Antisense oligonucleotide activity in tumour cells is influenced by intracellular LBPA distribution and extracellular vesicle recycling.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
01 11 2021
01 11 2021
Historique:
received:
01
10
2019
accepted:
08
10
2021
entrez:
2
11
2021
pubmed:
3
11
2021
medline:
21
12
2021
Statut:
epublish
Résumé
Next generation modified antisense oligonucleotides (ASOs) are commercially approved new therapeutic modalities, yet poor productive uptake and endosomal entrapment in tumour cells limit their broad application. Here we compare intracellular traffic of anti KRAS antisense oligonucleotide (AZD4785) in tumour cell lines PC9 and LK2, with good and poor productive uptake, respectively. We find that the majority of AZD4785 is rapidly delivered to CD63+late endosomes (LE) in both cell lines. Importantly, lysobisphosphatidic acid (LBPA) that triggers ASO LE escape is presented in CD63+LE in PC9 but not in LK2 cells. Moreover, both cell lines recycle AZD4785 in extracellular vesicles (EVs); however, AZD4785 quantification by advanced mass spectrometry and proteomic analysis reveals that LK2 recycles more AZD4785 and RNA-binding proteins. Finally, stimulating LBPA intracellular production or blocking EV recycling enhances AZD4785 activity in LK2 but not in PC9 cells thus offering a possible strategy to enhance ASO potency in tumour cells with poor productive uptake of ASOs.
Identifiants
pubmed: 34725463
doi: 10.1038/s42003-021-02772-0
pii: 10.1038/s42003-021-02772-0
pmc: PMC8560811
doi:
Substances chimiques
Antineoplastic Agents
0
Lysophospholipids
0
Monoglycerides
0
Oligodeoxyribonucleotides, Antisense
0
bis(monoacylglyceryl)phosphate
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1241Informations de copyright
© 2021. The Author(s).
Références
J Pharmacol Exp Ther. 2001 Feb;296(2):388-95
pubmed: 11160622
J Clin Invest. 1995 Apr;95(4):1814-23
pubmed: 7706488
Dev Cell. 2011 Oct 18;21(4):708-21
pubmed: 21962903
Nat Commun. 2021 Jul 19;12(1):4389
pubmed: 34282141
J Pharmacol Exp Ther. 1993 Dec;267(3):1181-90
pubmed: 8166890
Nat Cell Biol. 2007 Jun;9(6):654-9
pubmed: 17486113
Lancet. 2016 Nov 5;388(10057):2239-2253
pubmed: 27665230
PLoS One. 2015 Dec 21;10(12):e0145686
pubmed: 26690353
J Biol Chem. 1998 Aug 7;273(32):20121-7
pubmed: 9685355
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
EMBO J. 2002 Mar 15;21(6):1289-300
pubmed: 11889035
Proc Natl Acad Sci U S A. 1989 May;86(10):3474-8
pubmed: 2726730
Bioanalysis. 2011 Jun;3(12):1299-303
pubmed: 21679020
Drug Metab Dispos. 2007 Mar;35(3):460-8
pubmed: 17172312
Biochem Pharmacol. 2009 Aug 1;78(3):284-91
pubmed: 19393225
J Virol. 2016 Nov 28;90(24):11181-11196
pubmed: 27707921
Nat Cell Biol. 2010 Jan;12(1):19-30; sup pp 1-13
pubmed: 19966785
Adv Drug Deliv Rev. 2015 Jun 29;87:46-51
pubmed: 25666165
Nucleic Acid Ther. 2015 Oct;25(5):275-84
pubmed: 26176274
Traffic. 2020 Jan;21(1):76-93
pubmed: 31854087
J Biol Chem. 2002 Aug 30;277(35):32157-64
pubmed: 12065580
Lipids. 2015 Sep;50(9):907-12
pubmed: 26205346
Nanoscale. 2018 Aug 7;10(29):14230-14244
pubmed: 30010165
Science. 2008 Feb 29;319(5867):1244-7
pubmed: 18309083
Nucleic Acids Res. 2016 Apr 7;44(6):2782-94
pubmed: 26908652
Cells. 2019 Jan 10;8(1):
pubmed: 30634626
Cell. 1983 Jul;33(3):967-78
pubmed: 6307529
Nucleic Acids Res. 2019 May 21;47(9):4375-4392
pubmed: 30927008
Nature. 1998 Mar 12;392(6672):193-7
pubmed: 9515966
Nat Rev Mol Cell Biol. 2018 Apr;19(4):213-228
pubmed: 29339798
Mol Ther. 2017 Sep 6;25(9):2075-2092
pubmed: 28663102
J Cell Biol. 1983 Aug;97(2):329-39
pubmed: 6309857
Nucleic Acids Res. 2017 May 19;45(9):5309-5322
pubmed: 28379543
FEBS Lett. 2019 Aug;593(15):1983-1992
pubmed: 31175663
Anal Biochem. 1996 Mar 1;235(1):36-43
pubmed: 8850544
Nat Cell Biol. 1999 Jun;1(2):113-8
pubmed: 10559883
Mol Cell Proteomics. 2016 Jan;15(1):305-17
pubmed: 26545397
Sci Transl Med. 2017 Jun 14;9(394):
pubmed: 28615361
Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):E968-77
pubmed: 26858453
Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613
pubmed: 30476243
J Med Chem. 2009 Jan 8;52(1):10-3
pubmed: 19086780
EMBO Rep. 2019 Jul;20(7):e47055
pubmed: 31267706
J Cell Biol. 2020 Mar 2;219(3):
pubmed: 32049272
Science. 2004 Jan 23;303(5657):531-4
pubmed: 14739459
J Extracell Vesicles. 2018 Nov 23;7(1):1535750
pubmed: 30637094
Nucleic Acids Res. 2016 Sep 6;44(15):7314-30
pubmed: 27378781
Nucleic Acids Res. 2018 Apr 20;46(7):3579-3594
pubmed: 29514240
J Cell Biol. 2018 Mar 5;217(3):1129-1142
pubmed: 29339438
Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7595-9
pubmed: 1881900
Nat Commun. 2019 Sep 24;10(1):4333
pubmed: 31551417
Nat Biotechnol. 2013 Jul;31(7):653-8
pubmed: 23792629
Nat Biotechnol. 2017 Mar;35(3):230-237
pubmed: 28244996
Sci Adv. 2018 Oct 17;4(10):eaat3386
pubmed: 30345352
Nucleic Acids Res. 1997 Aug 15;25(16):3290-6
pubmed: 9241243
Nucleic Acids Res. 2011 Jun;39(11):4795-807
pubmed: 21345934
Nat Cell Biol. 2005 Jul;7(7):653-64
pubmed: 15951806