Caspases: Moonlighting proteins with theranostic potential

Abstract

Apoptosis evasion, a major hallmark of cancer, promotes tumour development and progression as well as chemoresistance and angiogenesis. Cancer cells resist apoptosis through a variety of strategies including downregulation of death receptors, overexpression of anti-apoptotic proteins, reduced expression of pro-apoptotic proteins, and dysregulation of caspases. Caspases are highly versatile, multifunctional proteolytic enzymes that are involved in both initiation and execution phases of apoptotic cell death. These enzymes are regulated by members of the inhibitor of apoptosis proteins (IAP) family and cellular FLICE inhibitory protein. Although caspases function as tumour suppressors in general, mutations, polymorphisms and their non-apoptotic roles render the involvement of caspases in tumorigenesis more complex and context-specific. Caspases have been extensively exploited as a therapeutic platform to reinstate apoptosis signalling as well as in chemo- and radio-sensitization of malignant tumours. A number of approaches and molecules have been developed to activate caspases for cancer therapeutics. These include SMAC mimetics, caspase activators, proteasomal and histone deacetylase inhibitors among several others. Although targeting caspases has shown promise, it is not clear whether they can be used in diverse malignancies given the pro-survival functions of these enzymes. Deeper insights into the varied functions of caspases will enable development of more effective and safer treatment options for diverse malignancies.