scholarly journals Antiandrogens Target TMPRSS2 and Reduce SARS-CoV-2 Virus Entry in Lung Cells

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A60-A61
Author(s):  
Damien A Leach ◽  
Mohr Andrea ◽  
Ralf Zwacka ◽  
Stathis Giottis ◽  
Laura Yates ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Surface ◽  
Human Lung ◽  
Surface Proteins ◽  
Host Cells ◽  
Mouse Lung ◽  
Lung Cells ◽  
Sequencing Data ◽  
Cell Surface Proteins ◽  
Human Lung Cells

Abstract The SARS-CoV-2 coronavirus is the cause of the COVID-19 pandemic. Entry of the virus into host cells, most destructively lung cells, requires two host cell surface proteins, ACE2 and TMPRSS2, downregulation of which is thus a potential therapeutic approach for COVID-19. Both of these cell surface proteins are steroid regulated: TMPRSS2 is a well-characterised androgen-regulated target in prostate cancer. Analysis of sequencing data shows co-expression of the androgen receptor (AR) and TMPRSS2 in key human lung cell types that are targeted by SARS- CoV-2. We show that treatment with antiandrogens such as enzalutamide (a well-tolerated drug widely used in advanced prostate cancer) significantly reduces TMPRSS2 levels in human lung cells and in vivo in mouse lung. We demonstrate that AR binding in the region of the TMPRSS2 gene differs between lung and prostate, identifying distinct regulatory regions. Together, the data and evidence presented supports clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

scholarly journals The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
D. A. Leach ◽  
A. Mohr ◽  
E. S. Giotis ◽  
E. Cil ◽  
A. M. Isac ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Human Lung ◽  
Cell Types ◽  
Receptor Activation ◽  
Surface Proteins ◽  
Mouse Lung ◽  
Lung Cells ◽  
Human Lung Cells ◽  
Cellular Entry ◽  
Experimental Data Analysis

AbstractSARS-CoV-2 attacks various organs, most destructively the lung, and cellular entry requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; androgen receptor activation increases TMPRSS2 levels in various tissues, most notably prostate. We show here that treatment with the antiandrogen enzalutamide—a well-tolerated drug widely used in advanced prostate cancer—reduces TMPRSS2 levels in human lung cells and in mouse lung. Importantly, antiandrogens significantly reduced SARS-CoV-2 entry and infection in lung cells. In support of this experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

scholarly journals Enzalutamide, a prostate cancer therapeutic, downregulates TMPRSS2 in lung and reduces cellular entry of SARS-CoV-2

2021 ◽  
Author(s):  
D. A. Leach ◽  
A. Mohr ◽  
E. S. Giotis ◽  
A. M. Isac ◽  
L. L. Yates ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Viral Entry ◽  
Human Lung ◽  
Therapeutic Potential ◽  
Cell Types ◽  
Surface Proteins ◽  
Lung Cells ◽  
Human Lung Cells ◽  
Transcription Factor Activation

Abstract The COVID-19 pandemic, caused by the novel human coronavirus SARS-CoV-2 coronavirus, attacks various organs but most destructively the lung. It has been shown that SARS-CoV-2 entry into lung cells requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; activation of the androgen receptor increases TMPRSS2 levels in various tissues, most notably the prostate. We show here that treatment with the antiandrogen enzalutamide – a well-tolerated drug widely used in advanced prostate cancer – reduces TMPRSS2 levels in human lung cells. Further, enzalutamide treatment of mice dramatically decreased Tmprss2 levels in the lung. To determine therapeutic potential, we assessed uptake of SARS-CoV-2 Spike protein pseudotyped lentivirus and live SARS-CoV-2 into human lung cells and saw a significant reduction in viral entry and infection upon treatment with the antiandrogens enzalutamide and bicalutamide. In support of this new experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types that are targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

scholarly journals Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide

2020 ◽  
Author(s):  
Fei Li ◽  
Ming Han ◽  
Pengfei Dai ◽  
Wei Xu ◽  
Juan He ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lung Cancer ◽  
Cancer Cells ◽  
Human Lung ◽  
Host Cells ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Lung Cells ◽  
Prostate Cancer Cells ◽  
Human Lung Cells

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat due to the lack of effective drugs or vaccines against SARS-CoV-2. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a relatively new antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry into host cells, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and SARS-CoV-2-infected Ad-ACE2-transduced Tmprss2 knockout (Tmprss2-KO) and wild-type (WT) mice. TMPRSS2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cancer cells (LNCaP) but not in human lung cancer cells or patient-derived lung organoids. Although Tmprss2 knockout effectively blocked SARS-CoV-2 infection in ACE2-transduced mice, enzalutamide showed no antiviral activity due to the AR independence of TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19.

scholarly journals TMPRSS2, required for SARS-CoV-2 entry, is downregulated in lung cells by enzalutamide, a prostate cancer therapeutic

2020 ◽  
Author(s):  
Damien A. Leach ◽  
Ana-Maria Isac ◽  
Charlotte L. Bevan ◽  
Greg N. Brooke
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Human Lung ◽  
Cell Types ◽  
Surface Proteins ◽  
Lung Cells ◽  
Human Lung Cells ◽  
Transcription Factor Activation ◽  
Host Cell Surface ◽  
Experimental Data Analysis

Abstract The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, attacks various organs but most destructively the lung. It has been shown that SARS-CoV-2 entry into lung cells requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; activation of the androgen receptor increases TMPRSS2 levels in various tissues, most notably the prostate. We show here that treatment with the antiandrogen enzalutamide – a well-tolerated drug widely used in advanced prostate cancer – reduces TMPRSS2 levels in human lung cells. Further, enzalutamide treatment of mice dramatically decreased Tmprss2 levels in the lung. In support of this new experimental data, analysis of existing datasets shows striking co- expression of AR and TMPRSS2, including in specific lung cell types that are targeted by SARS- CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

scholarly journals Single cell transcriptomic profiling identifies molecular phenotypes of newborn human lung cells

2020 ◽  
Author(s):  
Soumyaroop Bhattacharya ◽  
Jacquelyn L. Myers ◽  
Cameron Baker ◽  
Minzhe Guo ◽  
Soula Danopoulos ◽  
...  
Keyword(s):  
Single Cell ◽  
Lung Development ◽  
Human Lung ◽  
Development Program ◽  
Molecular Profile ◽  
Mouse Lung ◽  
Lung Cells ◽  
Analysis Tool ◽  
Human Lung Cells ◽  
Human And Mouse

AbstractWhile animal model studies have extensively defined mechanisms controlling cell diversity in the developing mammalian lung, the limited data available from late stage human lung development represents a significant knowledge gap. The NHLBI Molecular Atlas of Lung Development Program (LungMAP) seeks to fill this gap by creating a structural, cellular and molecular atlas of the human and mouse lung. Single cell RNA sequencing generated transcriptional profiles of 5500 cells obtained from two newborn human lungs from the LungMAP Human Tissue Core Biorepository. Frozen single cell isolates were captured, and library preparation was completed on the Chromium 10X system. Data was analyzed in Seurat, and cellular annotation was performed using the ToppGene functional analysis tool. Single cell sequence data from an additional 32000 postnatal day 1 through 10 mouse lung cells generated by the LungMAP Cincinnati Research Center was integrated with the human data. Transcriptional interrogation of newborn human lung cells identified distinct clusters representing multiple populations of epithelial, endothelial, fibroblasts, pericytes, smooth muscle, and immune cells and signature genes for each of these population. Computational integration of newborn human and postnatal mouse lung development cellular transcriptomes facilitated the identification of distinct epithelial lineages including AT1, AT2 and ciliated epithelial cells. Integration of the newborn human and mouse cellular transcriptomes also demonstrated cell type-specific differences in maturation states of newborn human lung cells. In particular, newborn human lung matrix fibroblasts could be separated into those representative of younger cells (n=393), or older cells (n=158). Cells with each molecular profile were spatially resolved within newborn human lung tissue. This is the first comprehensive molecular map of the cellular landscape of neonatal human lung, including biomarkers for cells at distinct states of maturity.

scholarly journals Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fei Li ◽  
Ming Han ◽  
Pengfei Dai ◽  
Wei Xu ◽  
Juan He ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Lung Cells ◽  
Global Public Health ◽  
Prostate Cancer Cells ◽  
Antiviral Efficacy ◽  
Prostate Cells ◽  
Human Lung Cells

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.

scholarly journals Analysis of cell surface proteins delineates a differentiation pathway linking endocrine and nonendocrine human lung cancers.

1983 ◽  
Vol 80 (12) ◽  
pp. 3807-3811 ◽  
Author(s):  
G. Goodwin ◽  
J. H. Shaper ◽  
M. D. Abeloff ◽  
G. Mendelsohn ◽  
S. B. Baylin
Keyword(s):  
Cell Surface ◽  
Human Lung ◽  
Surface Proteins ◽  
Cell Surface Proteins ◽  
Lung Cancers

What do nanometer molecular trajectories tell us about heterogeneous cell surface domaines?

1995 ◽  
Vol 53 ◽  
pp. 786-787
Author(s):  
Watt W. Webb
Keyword(s):  
Cell Surface ◽  
Lipid Membranes ◽  
Surface Proteins ◽  
Protein Diffusion ◽  
Coated Pits ◽  
Cell Surface Proteins ◽  
Membrane Heterogeneity ◽  
Fluorescence Photobleaching Recovery ◽  
Photobleaching Recovery ◽  
Plasma Membrane Heterogeneity

Plasma membrane heterogeneity is implicit in the existence of specialized cell surface organelles which are necessary for cellular function; coated pits, post and pre-synaptic terminals, microvillae, caveolae, tight junctions, focal contacts and endothelial polarization are examples. The persistence of these discrete molecular aggregates depends on localized restraint of the constituent molecules within specific domaines in the cell surface by strong intermolecular bonds and/or anchorage to extended cytoskeleton. The observed plasticity of many of organelles and the dynamical modulation of domaines induced by cellular signaling evidence evanescent intermolecular interactions even in conspicuous aggregates. There is also strong evidence that universal restraints on the mobility of cell surface proteins persist virtually everywhere in cell surfaces, not only in the discrete organelles. Diffusion of cell surface proteins is slowed by several orders of magnitude relative to corresponding protein diffusion coefficients in isolated lipid membranes as has been determined by various ensemble average methods of measurement such as fluorescence photobleaching recovery(FPR).

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