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MEK inhibitors reduce cellular expression of ACE2, pERK, pRb while stimulating NK-mediated cytotoxicity and attenuating inflammatory cytokines relevant to SARS-CoV-2 infection.
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; El-Deiry, Wafik S.
  • Zhou L; Brown Experimentalists Against COVID-19 (BEACON) Group, Brown University, Providence, RI 02912, USA.
  • Huntington K; Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
  • Zhang S; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
  • Carlsen L; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI 02912, USA.
  • So EY; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
  • Parker C; Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
  • Sahin I; Brown Experimentalists Against COVID-19 (BEACON) Group, Brown University, Providence, RI 02912, USA.
  • Safran H; Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
  • Kamle S; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI 02912, USA.
  • Lee CM; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
  • Geun Lee C; Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
  • A Elias J; Pathobiology Graduate Program, Brown University, Providence, RI 02912, USA
  • S Campbell K; Brown Experimentalists Against COVID-19 (BEACON) Group, Brown University, Providence, RI 02912, USA.
  • T Naik M; Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
  • J Atwood W; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
  • Youssef E; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI 02912, USA.
  • A Pachter J; Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
  • Navaraj A; Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
  • A Seyhan A; Brown Experimentalists Against COVID-19 (BEACON) Group, Brown University, Providence, RI 02912, USA.
  • Liang O; Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
  • El-Deiry WS; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI 02912, USA.
Oncotarget ; 11(46): 4201-4223, 2020 11 17.
Article in English | MEDLINE | ID: covidwho-948276
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.
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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Journal: Oncotarget Year: 2020 Document Type: Article Affiliation country: Oncotarget.27799

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Journal: Oncotarget Year: 2020 Document Type: Article Affiliation country: Oncotarget.27799