Androgen-deprivation therapy boosts MX1 expression, a silent effector against COVID-19.

SANCHIS, PABLO; SABATER, AGUSTINA; CASCARDO, FLORENCIA; LABANCA, ESTEFANIA; COTIGNOLA, JAVIER; LAGE VICKERS, SOFIA; ABBATE, MERCEDES; OLSZEVICKI, SANTIAGO; ORTIZ, EMILIANO G; GUERON, GERALDINE; BIZZOTTO JUAN; LAVIGNOLLE, ROSARIO; TORO, AYELÉN; ANSELMINO, NICOLÁS; ELBA VAZQUEZ

Filadelfia

Congreso; AACR Anual Meeting 2021; 2021

Cancer is a risk factor for SARS-CoV-2 infection. Recent reports have shown thatprostate cancer (PCa) patients undergoing androgen-deprivation therapies (ADT) were partiallyprotected from COVID-19. The human myxovirus resistance gene 1 (MX1) is expressed in many tissues, includingprostate, and we have previously demonstrated its antitumoral activity in PCa. This proteinparticipates in the antiviral response and It is an IFN-stimulated gene (ISGs), especially duringinfluenza virus infection. There are ongoing clinical trials for COVID-19 prevention and/ortreatment using type I or III interferons. However, IFN administration could enhance a "cytokine-storm" causing a hyper-inflammatory response and contributing to organ failure.In this work, we performed bioinformatics analyses in a case-control study from SARS-CoV-2 positive (n=403) and negative (n=50) patients. We analyzed the response to infectionassessing gene expression profiles in nasopharyngeal swabs of key host cell receptors (ACE2,TMPRSS2, BSG/CD147, CTSB, CTSL, ADAM17) and antiviral proteins (MX1, MX2, NRF2,IRF3, HIF1A, HMOX1).SARS-CoV-2 positive cases had higher ACE2, but lower TMPRSS2, BSG/CD147 andCTSB expression. Patient age negatively affected ACE2 expression. MX1 and MX2 were higherin SARS-CoV-2 positive individuals, and negative trends were observed as patients? ageincreased. Principal Component Analysis determined that ACE2, MX1, MX2 and BSG/CD147expressions were able to cluster non-COVID-19 and COVID-19 individuals. Multivariableregression showed that MX1 expression significantly increased for each unit of viral loadincrement.Given that MX1 was differentially expressed between COVID-19 and non-COVID-19patients, we evaluated MX1 expression in A549 and Calu3 lung cell lines. MX1 was significantlyup-regulated upon infection with SARS-CoV-2.Since ADT reduces SARS-CoV-2 infection incidence, we aim to study MX1 regulation bydihydrotestosterone (DHT). We browsed publicly available ChIP-seq experiments evaluatingandrogen receptor (AR) binding sites in different PCa cell lines under DHT stimulation. Resultsindicated enriched AR binding sites on the MX1 sequence. Therefore, we treated LNCaP cellswith DHT, observing a significant decrease in MX1 mRNA levels. Accordingly, we observed asignificant increase of MX1 gene expression in PCa patients after ADT treatment.In summary, our study findings support differences in ACE2, MX1, MX2 andBSG/CD147 expression between COVID-19 and non-COVID-19 patients; and point out to MX1as a critical responder in SARS-CoV-2 infection. Furthermore, we demonstrated MX1modulation by ADT. Taking into consideration the fact that PCa patients that underwent ADTwere less prone to present the infection, we propose this gene as an alternative druggabletarget for COVID-19 patients, especially those with PCa as a previous condition.