RIPK1-targeting in cancer: modulation of programmed cell death process for cancer treatment

PURPOSE: Programmed cell death (PCD) is an important cellular event responsible for the maintenance of cellular homeostasis. More studies have suggested that the imbalance between cell survival and cell death leads to tumorigenesis, a process in which cells escape from PCDs. INTRODUCTION: Among the well-known cell death pathways, necroptosis has been defined to be a regulated necrotic cell death, which mediators belong both to the apoptotic and necrotic pathways [1]. The process can be triggered by a variety of stimuli and requires the activation of receptor-interacting protein (RIP) kinases RIPK1 and RIPK3, as well as mixed lineage kinase domain-like protein (MLKL) [2]. RESULTS AND CONCLUSIONS: A recent study has correlated the acetylation of RIP to the tumorigenesis and cell death process. The molecular complex mediated by RIPK1 shows the co-presence of proteins with different enzymatic activities such as acetyltransferase, kinase and deacetylase elucidating cancer not only as a genetic but also an epigenetic disease [3]. Since RIPK1 is overexpressed in several cancer cell types and it is involved in either survival or apoptosis and necroptosis, one of the main goals of the project is to determine how to modulate the RIP1-complex, in order to lead malignant cells to cell death. To reach this aim, the interactome study in leukaemia cell line will be performed to clarify the involvement of RIPK1. While the roles of RIPK3 and MLKL in leukemogenesis are already known, the novelty is to understand “how” RIPK1 triggers different cellular pathways that leads cells to make a critical decision either to survive or die. Starting from the characterization of Necrostatins, the project includes the identification of new modulators of RIPK1 which could regulate the activated molecular complex in different cellular processes and eventually to make necroptosis a pharmacologically controllable event.