The COVID-19 pandemic is expected to have an adverse effect on the progression of multiple cancers, including prostate cancer, due to the ensuing cytokine storm and associated oncogenic signaling. Epidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation of SARS-CoV-2 host cell receptor ACE2 and co-receptor TMPRSS2 by androgen in mouse tissues and human prostate and lung cell lines. Additionally, we demonstrate the endogenous interaction between TMPRSS2 and ACE2 in human cells and validate ACE2 as a TMPRSS2 substrate. In an overexpression model, and the prostate and lung cells, Camostat – a TMPRSS2 inhibitor, blocked the cleavage of pseudotype SARS-CoV-2 surface Spike without disrupting TMPRSS2-ACE2 interaction. Thus providing evidence for the first time a direct role of TMPRSS2 in priming the SARS-CoV-2 Spike protein, required for viral fusion to the host cell. Importantly, androgen-deprivation, anti-androgens such as enzalutamide/AR-PROTAC, or Camostat treatment attenuated the SARS-CoV-2 S-mediated entry in lung and prostate cells. Together, our preclinical data provide a strong rationale for clinical evaluations of the TMPRSS2 inhibitors, androgen-deprivation therapy and androgen receptor antagonists alone or in combination with anti-viral drugs as early as clinically possible to prevent inflammation driven COVID-19 progression.

中文翻译：

---

靶向雄激素调节TMPRSS2和ACE2作为对抗COVID-19的治疗策略

由于随之而来的细胞因子风暴和相关的致癌信号，预计COVID-19大流行会对包括前列腺癌在内的多种癌症的发展产生不利影响。流行病学数据显示，男性COVID-19的严重程度和死亡率增加，表明雄激素可能在SARS-CoV-2感染中发挥作用。在这里，我们提供了雄激素在小鼠组织以及人前列腺和肺细胞系中对SARS-CoV-2宿主细胞受体ACE2和共受体TMPRSS2的转录调控的证据。此外，我们证明了人类细胞中TMPRSS2和ACE2之间的内源性相互作用，并验证了ACE2作为TMPRSS2底物。在过表达模型以及前列腺和肺细胞中，Camostat –一种TMPRSS2抑制剂，在不破坏TMPRSS2-ACE2相互作用的情况下，阻断了SARS-CoV-2型假穗突型的切割。因此，首次提供了证据，TMPRSS2在引发SARS-CoV-2 Spike蛋白引发病毒融合到宿主细胞中起直接作用。重要的是，剥夺雄激素，使用抗雄激素药（例如enzalutamide / AR-PROTAC或Camostat治疗）会减弱SARS-CoV-2 S介导的肺和前列腺细胞的进入。总之，我们的临床前数据为TMPRSS2抑制剂，雄激素剥夺疗法和雄激素受体拮抗剂单独或与抗病毒药物联用的临床评估提供了强大的理论依据，可在临床上尽早预防炎症驱动的COVID-19进展。病毒融合到宿主细胞中需要。重要的是，剥夺雄激素，使用抗雄激素药（例如enzalutamide / AR-PROTAC或Camostat治疗）会减弱SARS-CoV-2 S介导的肺和前列腺细胞的进入。总之，我们的临床前数据为TMPRSS2抑制剂，雄激素剥夺疗法和雄激素受体拮抗剂单独或与抗病毒药物联用的临床评估提供了强大的理论依据，可在临床上尽早预防炎症驱动的COVID-19进展。病毒融合到宿主细胞中需要。重要的是，剥夺雄激素，使用抗雄激素药（例如enzalutamide / AR-PROTAC或Camostat治疗）会减弱SARS-CoV-2 S介导的肺和前列腺细胞的进入。总之，我们的临床前数据为TMPRSS2抑制剂，雄激素剥夺疗法和雄激素受体拮抗剂单独或与抗病毒药物联用的临床评估提供了强大的理论依据，可在临床上尽早预防炎症驱动的COVID-19进展。