Old, new and emerging functions of caspases

Abstract

Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

“…While no change in protein levels of PUMA, another p53 target that mediates DNA damage was observed, following DEN treatment control Casp2 −/− mice had elevated puma gene expression (Supplementary Figure 6d), which correlates with the observations that DNA damage is already higher in ageing Casp2 −/− mice. 22 Levels of noxa, another proapoptotic BH3-only protein, remained unchanged (Supplementary Figure 6e).…”

“…[14][15][16][17][18][19][20] Metabolic state is another important regulator of HCC progression and there is increasing evidence that caspase-2 has a subtle role in regulating this process. 21,22 Caspase-2 deficiency in mice results in metabolic perturbations and aged caspase-2 mice show increased oxidative stress and DNA damage. 5,21,23 DEN-induced tumour formation involves the generation of DNA adducts, 10 and human HCC is commonly associated with genomic instability.…”

Advanced oxidation protein products induce pre‐osteoblast apoptosis through a nicotinamide adenine dinucleotide phosphate oxidase‐dependent, mitogen‐activated protein kinases‐mediated intrinsic apoptosis pathway

“…The intrinsic apoptosis pathway is a form of programed cell death which mainly characterized by mitochondria dysfunction (Shalini, Dorstyn, Dawar & Kumar, 2015; Tower, 2015). In this process, stimulation such as oxidative stress decreases the ▵Ψm, increases expression of BAX, and decreases Bcl‐2, and then results in mitochondrial membrane permeabilization and the releases of cytochrome c into cytoplasm, activates a series of pro‐apoptotic protein, and leads to cell death (Tower, 2015).…”

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

“…They are produced as inactive zymogens that are activated either through incorporation into large protein complexes, such as the apoptosome (initiator caspases), or by proteolytic processing (effector caspases). 41,42 After activation in the apoptosome, initiator caspases such as caspase-9 and its Drosophila ortholog Dronc (death regulator Nedd2-like caspase), cleave and activate effector caspases, such as caspase-3 and its Drosophila ortholog DrICE (deathrelated ICE-like protease). 40,43 The activity of caspases is controlled at multiple levels.…”