Making Connections: p53 and the Cathepsin Proteases as Co-Regulators of Cancer and Apoptosis

Simple Summary This article describes an emerging area of significant interest in cancer and cell death and the relationships shared by these through the p53 and cathepsin proteins. While it has been demonstrated that the p53 protein can directly induce the leakage of cathepsin proteases from the lysosome, directly triggering cell death, little is known about what factors set the threshold at which the lysosome can become permeabilized. It appears that the expression levels of cathepsin proteases may be central to this process, with some of them being transcriptionally regulated by p53. The consequences of such a mechanism have serious implications for lysosomal-mediated apoptosis and have significant input into the design of therapeutics and their strategic use. In this review, we highlight the importance of extending such findings to other cathepsin family members and the need to assess the roles of p53 isoforms and mutants in furthering this mechanism. While viewed as the "guardian of the genome", the importance of the tumor suppressor p53 protein has increasingly gained ever more recognition in modulating additional modes of action related to cell death. Slowly but surely, its importance has evolved from a mutated genetic locus heavily implicated in a wide array of cancer types to modulating lysosomal-mediated cell death either directly or indirectly through the transcriptional regulation of the key signal transduction pathway intermediates involved in this. As an important step in determining the fate of cells in response to cytotoxicity or during stress response, lysosomal-mediated cell death has also become strongly interwoven with the key components that give the lysosome functionality in the form of the cathepsin proteases. While a number of articles have been published highlighting the independent input of p53 or cathepsins to cellular homeostasis and disease progression, one key area that warrants further focus is the regulatory relationship that p53 and its isoforms share with such proteases in regulating lysosomal-mediated cell death. Herein, we review recent developments that have shaped this relationship and highlight key areas that need further exploration to aid novel therapeutic design and intervention strategies.