Ricerc@Sapienza

To face cellular stress caused by extracellular and intracellular insults, cancer cells trigger protective responses such as the Unfolded Protein Response (UPR) that mainly helps to cope with proteotoxic stress and DNA damage response (DDR) that mainly protects from genotoxic stress. However, these two processes comunicate, as proteotoxic stress may also induce DNA damage and radiations, that classically cause DNA damage, also activate ER stress/UPR. The main UPR sensors, namely Ire1 alpha, PERK and ATF6, have been reported to modulate the expression/activity of molecules involved in DNA repair, either in the homologouous repair (HR) and non-homologous end joining repair (NHEJ) pathways.
Moreover, both the intensity of UPR and DDR are regulated by kinase such as ERK1/2 that plays a key role in preventing the pro-death effect of UPR. Indeed, ERK1/2 plays a role in the up-regulation of UPR pro-survival molecule BIP. In addition, the key pro-apoptotic UPR molecule CHOP has been reported to dephosphorylate ERK1/2 in order to induce cell death. This effect is mainly mediated by the upregulation of DUSP5, a dual-specific phosphatase that amog other targets acts on ERK1/2. ERK1/2 also prevents cell death in the course of genotoxic stress. Interestingly, p53, that can be activated by both genotoxic and proteotoxic stress, can also upregulate DUSP5 in order to dephosphorylate ERK1/2 and activate its pro-apototic targets such as Puma.
Based on this background, we will study the interplay between UPR activation and DDR in cancer cells in which ER stress will be induced by drugs such as thapsigargin and genotoxic stress induced by radiations or genotoxic drugs. Then, UPR will be manipulated to strenghten the pro-death effects of genotoxis stress or DDR molecules will be inhibited to potentiate the effect of genotoxic stress. p53 activation and ERK1/2 phosphorylation and their interplay on DNA damage and the balance between life and death will be explored.