BH3-only proteins in cancer and apoptosis

In multicellular organisms, an enormous number of cells die every day, because of stress, injury, infection, or natural turnover necessary for proper tissue homeostasis. In most of these events, cell death is orchestrated by the dying cell itself, a sort of cellular suicide called apoptosis. Malfunctioning of this death program at any stage leads to severe human diseases, including cancer and autoimmune disorders. Apoptosis is elicited by intracellular or extracellular stimuli that activate a common cell death machinery, culminating in permeabilization of the mitochondrial membrane. In this chapter we describe the state of the art of the knowledge of how cells execute mitochondrial or intrinsic apoptosis. A fundamental and crucial role regulator to the comments apoptosis is assumed by BH3-only proteins, a class of small molecules belonging to the Bcl-2 family. They are both sensors of death signals and vectors of information to the core apoptotic machinery, exerting their activity by hierarchical and finely tuned interactions with the other Bcl-2 family members. We discuss the groundbreaking research from several laboratories that have contributed to disclosing the complex activity of BH3-only proteins and the efforts made to translate these results into novel tools for cancer therapy.