Prostate apoptosis response-4 and tumor suppression: it's not just about apoptosis anymore

Abstract

The tumor suppressor prostate apoptosis response-4 (Par-4) has recently turned 'twenty-five'. Beyond its indisputable role as an apoptosis inducer, an increasing and sometimes bewildering, new roles for Par-4 are being reported. These roles include its ability to regulate autophagy, senescence, and metastasis. This growing range of responses to Par-4 is reflected by our increasing understanding of the various mechanisms through which Par-4 can function. In this review, we summarize the existing knowledge on Par-4 tumor suppressive mechanisms, and discuss how the interaction of Par-4 with different regulators influence cell fate. This review also highlights the new secretory pathway that has emerged and the likely discussion on its clinical implications.

Fig. 1. Schematic representation of human Par-4.

The functional domains and some of the sites of post-translational modification are illustrated.

Fig. 2. Par-4 interacting proteins.

Some of the important positive and negative regulators of Par-4 functions are illustrated. See text for details.

Fig. 3. The canonical Par-4 functions.

The extrinsic and intrinsic apoptotic pathway regulated by Par-4 is illustrated. The extrinsic cell death is initiated by the ligation of death-inducing ligands (TNFα, FasL, and TRAIL) to their cognate receptors (TNF receptor, Fas receptor, and death receptors-DR4/DR5). The ligation recruits adaptor proteins and pro-caspases, leading to the assembly of the DISC and the activation of caspase signaling cascade. The intrinsic pathway is characterized by permeabilization and depolarization of the mitochondrial membrane, leading to the release of apoptogenic factors such as cytochrome c, AIF, Smac/DIABLO, etc. Once released, these factors activate caspase signaling cascade and orchestrate the cell death process. Apoptosis is highly regulated by a variety of pro-apoptotic and anti-apoptotic proteins. The members of the Bcl-2 family of proteins are the central regulators of the intrinsic apoptotic pathway. Bcl-2 family proteins composed of both pro-apoptotic (e.g., Bad, Bid, Bax, Bak, Bcl-Xs, Bim, etc.) and anti-apoptotic (e.g., Bcl-2, Bcl-xL, Mcl-1, etc.) members. The balance between these two family members determines whether or not a cell will undergo apoptosis. tBid, truncated Bid; MMP, mitochondrial membrane permeabilization; DISC, death-inducing signaling complex.

Fig. 4. Caspase-mediated cleavage of Par-4.

Caspase-dependent post-translational regulation of par-4 is illustrated. See text for details. Ub, ubiquitination.

Fig. 5. Par-4 secretion and secretagogues.

Par-4 secretory pathway, important regulators of Par-4 secretion, and mechanism of Par-4 secretagogues are illustrated. See text for details.

Fig. 6. Schematic representation of Par-4 role in metastasis.

Proposed mechanism of Par-4-dependent inhibition of metastasis are illustrated. See text for details.

Fig. 7. Major milestones in Par-4 research.

Timeline highlighting crucial discoveries that provided insights into Par-4 functions and regulation.