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

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.

Roles of steroid receptors in the lung and COVID-19

“…In prostate cancer cell lines, androgens and anti-androgens have been reported to regulate ACE2 expression [ 39 , 87 ], and studies in mouse whole lung tissue support this [ 88 ]. However, in other studies, ACE2 was not seen to be androgen- or antiandrogen-regulated in lung cell lines or mouse lung tissue at the RNA level [ 13 , 56 ]. Another means of androgen/AR signalling influencing viral entry is by TMPRSS2 regulation.…”

“…ACE2 expression correlates with age, and has been reported as increased in males compared with females both generally and within the lung [ 26 , 52–55 ]. Whether TMPRSS2 expression is higher in male lungs than female is controversial, with some studies reporting a slight but significant difference [ 56 , 57 ] but others reporting no significant difference [ 58 , 59 ]. More generally, there are also gender disparities in response to viral infections, with females producing stronger immune responses and better clearance of viral loads [ 60 ].…”

“…Another means of androgen/AR signalling influencing viral entry is by TMPRSS2 regulation. TMPRSS2 is a well-known transcriptional target of AR in prostate cancer cells, and has recently been shown to be regulated by androgens and anti-androgens also in lung cells and mouse lung tissue [ 13 , 56 ]. Anti-androgens can also inhibit both pseudotyped and live SARS-CoV-2 viral entry in prostate cancer cells [ 39 ] and, more importantly, human lung cells [ 56 ].…”

“…TMPRSS2 is a well-known transcriptional target of AR in prostate cancer cells, and has recently been shown to be regulated by androgens and anti-androgens also in lung cells and mouse lung tissue [ 13 , 56 ]. Anti-androgens can also inhibit both pseudotyped and live SARS-CoV-2 viral entry in prostate cancer cells [ 39 ] and, more importantly, human lung cells [ 56 ]. Furthermore, anti-androgen inhibition of SARS-CoV-2 entry into lung cells was shown to be concomitant with down-regulation of TMPRSS2, and to occur even in cells stably overexpressing ACE2, supporting a pivotal role for TMPRSS2 down-regulation in the inhibitory effect of anti-androgens on virus entry.…”

“…Furthermore, anti-androgen inhibition of SARS-CoV-2 entry into lung cells was shown to be concomitant with down-regulation of TMPRSS2, and to occur even in cells stably overexpressing ACE2, supporting a pivotal role for TMPRSS2 down-regulation in the inhibitory effect of anti-androgens on virus entry. The specificity of this inhibitory effect of anti-androgens is emphasised by the presence of androgen response elements (AREs), known to bind AR, within the regulatory regions of TMPRSS2 ( Figure 3 B) [ 56 , 89 ].…”