MEK inhibitors reduce cellular expression of ACE2, pERK, pRb while stimulating NK-mediated cytotoxicity and attenuating inflammatory cytokines relevant to SARS-CoV-2 infection.
ACE2
COVID-19
SARS-CoV-2
TMPRSS2
pseudovirus
Journal
Oncotarget
ISSN: 1949-2553
Titre abrégé: Oncotarget
Pays: United States
ID NLM: 101532965
Informations de publication
Date de publication:
17 11 2020
17 11 2020
Historique:
received:
05
10
2020
accepted:
17
10
2020
entrez:
27
11
2020
pubmed:
28
11
2020
medline:
28
11
2020
Statut:
epublish
Résumé
COVID-19 affects vulnerable populations including elderly individuals and patients with cancer. Natural Killer (NK) cells and innate-immune TRAIL suppress transformed and virally-infected cells. ACE2, and TMPRSS2 protease promote SARS-CoV-2 infectivity, while inflammatory cytokines IL-6, or G-CSF worsen COVID-19 severity. We show MEK inhibitors (MEKi) VS-6766, trametinib and selumetinib reduce ACE2 expression in human cells. In some human cells, remdesivir increases ACE2-promoter luciferase-reporter expression, ACE2 mRNA and protein, and ACE2 expression is attenuated by MEKi. In serum-deprived and stimulated cells treated with remdesivir and MEKi we observed correlations between pRB, pERK, and ACE2 expression further supporting role of proliferative state and MAPK pathway in ACE2 regulation. We show elevated cytokines in COVID-19-(+) patient plasma (
Identifiants
pubmed: 33245731
doi: 10.18632/oncotarget.27799
pii: 27799
pmc: PMC7679035
doi:
Types de publication
Journal Article
Langues
eng
Pagination
4201-4223Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM119943
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM122732
Pays : United States
Informations de copyright
Copyright: © 2020 Zhou et al.
Déclaration de conflit d'intérêts
CONFLICTS OF INTEREST E.Y. and J.A.P. are employees and stockholders of Verastem Oncology. None of the other co-authors have disclosed relationships that are relevant for this work.
Références
Cell Death Discov. 2020 Jul 6;6:57
pubmed: 32655895
Lancet. 2020 Jun 20;395(10241):1907-1918
pubmed: 32473681
Cancer Cell. 2007 Jul;12(1):66-80
pubmed: 17613437
J Gen Virol. 2005 Aug;86(Pt 8):2269-2274
pubmed: 16033974
J Thromb Thrombolysis. 2020 Jul;50(1):54-67
pubmed: 32415579
J Virol. 2010 Aug;84(15):7703-12
pubmed: 20484496
Cell Res. 2020 May;30(5):367-369
pubmed: 32346073
Nat Commun. 2020 May 1;11(1):2176
pubmed: 32358491
JAMA. 2020 Aug 4;324(5):455-457
pubmed: 32492105
Curr Probl Cardiol. 2020 Aug;45(8):100618
pubmed: 32439197
JAMA. 2020 Aug 25;324(8):782-793
pubmed: 32648899
Adv Biol Regul. 2020 Aug;77:100737
pubmed: 32773100
Cell Host Microbe. 2020 Sep 9;28(3):486-496.e6
pubmed: 32738193
Shock. 2020 Oct;54(4):438-450
pubmed: 32649367
Mayo Clin Proc. 2020 Jul;95(7):1454-1466
pubmed: 32561148
Lancet. 2020 Jun 20;395(10241):1919-1926
pubmed: 32473682
Nature. 2020 Jul;583(7814):15-16
pubmed: 32606457
Nat Rev Clin Oncol. 2020 Jul;17(7):395-417
pubmed: 32203277
N Engl J Med. 2020 Apr 30;382(18):1708-1720
pubmed: 32109013
J Clin Invest. 2018 Jun 1;128(6):2325-2338
pubmed: 29533922
Hum Gene Ther. 2007 May;18(5):413-22
pubmed: 17518614
Arch Virol. 2015 Sep;160(9):2293-300
pubmed: 26138557
Curr Opin Virol. 2016 Feb;16:15-23
pubmed: 26590692
Cell. 2020 Aug 20;182(4):812-827.e19
pubmed: 32697968
Eur J Immunol. 2001 Nov;31(11):3138-46
pubmed: 11745330
Am J Physiol Cell Physiol. 2008 Nov;295(5):C1169-74
pubmed: 18768926
N Engl J Med. 2020 Nov 5;383(19):1827-1837
pubmed: 32459919
N Engl J Med. 2020 Jun 11;382(24):2372-2374
pubmed: 32302078
Crit Care Med. 2016 Aug;44(8):e711-20
pubmed: 27031380
Lancet Rheumatol. 2020 Aug;2(8):e474-e484
pubmed: 32835257
Nat Immunol. 2018 Aug;19(8):800-808
pubmed: 30026479
Front Physiol. 2017 Jan 18;7:682
pubmed: 28149280
N Engl J Med. 2020 May 21;382(21):2005-2011
pubmed: 32220208
J Glob Infect Dis. 2020 May 22;12(2):47-93
pubmed: 32773996
Lancet Respir Med. 2020 Jul;8(7):738-742
pubmed: 32416769
J Clin Invest. 2008 Jan;118(1):111-23
pubmed: 18079962
Lancet Psychiatry. 2020 Oct;7(10):875-882
pubmed: 32593341
Lancet Oncol. 2020 Jul;21(7):904-913
pubmed: 32479787
Cell Host Microbe. 2020 Sep 9;28(3):475-485.e5
pubmed: 32735849
Cell. 2020 Aug 6;182(3):685-712.e19
pubmed: 32645325
Nat Genet. 1997 Oct;17(2):141-3
pubmed: 9326928
Eur Respir J. 2020 May 14;55(5):
pubmed: 32217650
Lancet Neurol. 2020 Sep;19(9):767-783
pubmed: 32622375
Expert Rev Precis Med Drug Dev. 2018;3(3):197-204
pubmed: 30740527
N Engl J Med. 2020 Nov 5;383(19):1813-1826
pubmed: 32445440
Cell. 2020 Apr 16;181(2):271-280.e8
pubmed: 32142651
J Pharmacol Exp Ther. 2015 Feb;352(2):346-57
pubmed: 25503387
N Engl J Med. 2020 May 21;382(21):2012-2022
pubmed: 32227758
Nature. 2020 Jul;583(7816):469-472
pubmed: 32408336
Nat Rev Immunol. 2020 Jun;20(6):363-374
pubmed: 32346093
Int J Chron Obstruct Pulmon Dis. 2019 Nov 26;14:2611-2624
pubmed: 32063702
Nature. 2020 Oct;586(7827):113-119
pubmed: 32707573
J Exp Med. 2001 Mar 19;193(6):661-70
pubmed: 11257133