Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis

Abstract

Caspase-3 is a widely expressed member of a conserved family of proteins, generally recognized for their activated proteolytic roles in the execution of apoptosis in cells responding to specific extrinsic or intrinsic inducers of this mode of cell death. However, accumulating evidence indicates that caspase-3 also plays key roles in regulating the growth and homeostatic maintenance of both normal and malignant cells and tissues in multicellular organisms. Given that yeast possess an ancestral caspase-like gene suggests that the caspase-3 protein may have acquired different functions later during evolution to better meet the needs of more complex multicellular organisms, but without necessarily losing all of the functions of its ancestral yeast precursor. This review provides an update on what has been learned about these interesting dichotomous roles of caspase-3, their evolution, and their potential relevance to malignant as well as normal cell biology.

Figure 1.

Schematic illustrating caspase-dependent apoptosis-induced release of factors that then promote the proliferation of adjacent tumor and endothelial cells (Cheng et al., 2019; Feng et al., 2017; Kurtova et al., 2015; Lin et al., 2018; Tong et al., 2018). Apoptotic cells promote the proliferation of adjacent cells through AiP. This process is mediated by active caspase-3, which activates different signaling pathways leading to enhanced angiogenesis, tumor repopulation, and wound healing.

Figure 2.

Examples of mechanisms regulating cell cycle progression, differentiation, and tumorigenesis mediated by intrinsic caspase-3 cleavage of specific target proteins (Dick et al., 2015; Gabet et al., 2011; Larsen et al., 2010; Man et al., 2017; Naarmann-de Vries et al., 2013; Yosefzon et al., 2018). Caspase-3 mediated proteolytic activity regulates a variety of cellular processes by the cleavage of downstream targets.

Figure 3.

Conservation of non-apoptotic cellular processes mediated by caspase from yeast to mammals. Yeast Yca1 regulates protein quality control in catalytic and non-catalytic manners similar to catalytic and non-catalytic involvement of Drosophila effector caspases in autophagy.