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Zhou L , Huntington K , Zhang S , Carlsen L , So EY , Parker C , Sahin I , Safran H , Kamle S , Lee CM , Geun Lee C , Elias J , Campbell K S , Naik MT , Atwood WJ , Youssef E , Pachter JA , Navaraj A , Seyhan AA , Liang O , El-Deiry WS
MEK inhibitors reduce cellular expression of ACE2, pERK, pRb while stimulating NK-mediated cytotoxicity and attenuating inflammatory cytokines relevant to SARS-CoV-2 infection
Oncotarget. 2020 Nov 17;11(46) :4201-4223
PMID: 33245731    PMCID: PMC7679035    URL: https://www.ncbi.nlm.nih.gov/pubmed/33245731
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Abstract
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 (N = 9) versus control (N = 11). TMPRSS2, inflammatory cytokines G-CSF, M-CSF, IL-1α, IL-6 and MCP-1 are suppressed by MEKi alone or with remdesivir. We observed MEKi stimulation of NK-cell killing of target-cells, without suppressing TRAIL-mediated cytotoxicity. Pseudotyped SARS-CoV-2 virus with a lentiviral core and SARS-CoV-2 D614 or G614 SPIKE (S) protein on its envelope infected human bronchial epithelial cells, small airway epithelial cells, or lung cancer cells and MEKi suppressed infectivity of the pseudovirus. We show a drug class-effect with MEKi to stimulate NK cells, inhibit inflammatory cytokines and block host-factors for SARS-CoV-2 infection leading also to suppression of SARS-CoV-2-S pseudovirus infection of human cells. MEKi may attenuate SARS-CoV-2 infection to allow immune responses and antiviral agents to control disease progression.
Notes
1949-2553 Zhou, Lanlan Huntington, Kelsey Zhang, Shengliang Carlsen, Lindsey So, Eui-Young Parker, Cassandra Sahin, Ilyas Safran, Howard Kamle, Suchitra Lee, Chang-Min Geun Lee, Chun A Elias, Jack S Campbell, Kerry T Naik, Mandar J Atwood, Walter Youssef, Emile A Pachter, Jonathan Navaraj, Arunasalam A Seyhan, Attila Liang, Olin S El-Deiry, Wafik P20 GM119943/GM/NIGMS NIH HHS/United States U54 GM115677/GM/NIGMS NIH HHS/United States Journal Article Oncotarget. 2020 Nov 17;11(46):4201-4223. doi: 10.18632/oncotarget.27799. eCollection 2020 Nov 17.