Live and let die: signaling AKTivation and UPRegulation dynamics in SARS-CoVs infection and cancer

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic. Of particular interest for this topic are the signaling cascades that regulate cell survival and death, two opposite cell programs whose control is hijacked by viral infections. The AKT and the Unfolded Protein Response (UPR) pathways, which maintain cell homeostasis by regulating these two programs, have been shown to be deregulated during SARS-CoVs infection as well as in the development of cancer, one of the most important comorbidities in relation to COVID-19. Recent evidence revealed two way crosstalk mechanisms between the AKT and the UPR pathways, suggesting that they might constitute a unified homeostatic control system. Here, we review the role of the AKT and UPR pathways and their interaction in relation to SARS-CoV-2 infection as well as in tumor onset and progression. Feedback regulation between AKT and UPR pathways emerges as a master control mechanism of cell decision making in terms of survival or death and therefore represents a key potential target for developing treatments for both viral infection and cancer. In particular, drug repositioning, the investigation of existing drugs for new therapeutic purposes, could significantly reduce time and costs compared to de novo drug discovery.