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
Lanlan ZhouWafik S El-Deiry

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...Continue Reading

References

Nov 5, 1997·Nature Genetics·G S WuW S el-Deiry
Dec 18, 2001·European Journal of Immunology·K SatoK Ogasawara
Jul 22, 2005·The Journal of General Virology·Shuetsu FukushiShigeru Morikawa
Dec 15, 2007·The Journal of Clinical Investigation·Niklas FinnbergWafik S El-Deiry
Sep 5, 2008·American Journal of Physiology. Cell Physiology·Patricia E GallagherE Ann Tallant
Nov 23, 2015·Current Opinion in Virology·Stephen N WaggonerCarolyn E Rydyznski
Mar 14, 2018·The Journal of Clinical Investigation·Jessica WagnerWafik S El-Deiry
Jul 22, 2018·Nature Immunology·Quirin HammerChiara Romagnani
Feb 12, 2019·Expert Review of Precision Medicine and Drug Development·Marie D Ralff, Wafik S El-Deiry
Feb 18, 2020·International Journal of Chronic Obstructive Pulmonary Disease·Nisha KurianDanen M Cunoosamy
Feb 29, 2020·The New England Journal of Medicine·Wei-Jie GuanUNKNOWN China Medical Treatment Expert Group for Covid-19
Mar 24, 2020·Nature Reviews. Clinical Oncology·Benedito A Carneiro, Wafik S El-Deiry
Mar 29, 2020·The European Respiratory Journal·Wei-Jie GuanUNKNOWN China Medical Treatment Expert Group for Covid-19
Mar 29, 2020·The New England Journal of Medicine·Temet M McMichaelUNKNOWN Public Health–Seattle and King County, EvergreenHealth, and CDC COVID-19 Investigation Team
Apr 1, 2020·The New England Journal of Medicine·Pavan K BhatrajuCarmen Mikacenic
Apr 18, 2020·The New England Journal of Medicine·Parag GoyalMonika M Safford
Apr 30, 2020·Cell Research·Wei Cao, Taisheng Li
Apr 30, 2020·Nature Reviews. Immunology·Matthew Zirui TayLisa F P Ng
May 15, 2020·Nature·Denisa BojkovaChristian Münch
May 18, 2020·Journal of Thrombosis and Thrombolysis·Richard C Becker
May 18, 2020·The Lancet. Respiratory Medicine·Claudio RoncoFaeq Husain-Syed
May 23, 2020·Current Problems in Cardiology·Sevim ZaimAmer Harky
May 24, 2020·The New England Journal of Medicine·John H BeigelUNKNOWN ACTT-1 Study Group Members
May 28, 2020·The New England Journal of Medicine·Jason D GoldmanUNKNOWN GS-US-540-5773 Investigators
Jun 1, 2020·Lancet·Nicole M KudererUNKNOWN COVID-19 and Cancer Consortium
Jun 4, 2020·JAMA : the Journal of the American Medical Association·Arturo CasadevallLiise-Anne Pirofski
Jun 9, 2020·BioRxiv : the Preprint Server for Biology·M Eugenia DieterleRohit K Jangra
Jun 21, 2020·Mayo Clinic Proceedings·Prakhar VijayvargiyaRaymund R Razonable
Jul 1, 2020·The Lancet. Psychiatry·Aravinthan VaratharajUNKNOWN CoroNerve Study Group
Jul 6, 2020·Lancet Neurology·Mark A EllulTom Solomon
Jul 10, 2020·Cell·Mehdi BouhaddouNevan J Krogan
Jul 11, 2020·JAMA : the Journal of the American Medical Association·W Joost WiersingaHallie C Prescott
Jul 11, 2020·Shock·Yan LeyfmanIrshad H Chaudry
Jul 14, 2020·Cell Death Discovery·Ilyas SahinWafik S El-Deiry

❮ Previous
Next ❯

Methods Mentioned

BETA
transfection
fluorescence microscopy
X-ray
fluorescence
flow cytometry
ELISA
Assay

Related Concepts

Related Feeds

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.