Intrinsically Connected: Therapeutically Targeting the Cathepsin Proteases and the Bcl-2 Family of Protein Substrates as Co-regulators of Apoptosis.

Surinder M Soond,Lyudmila V Savvateeva,Maria V Kozhevnikova,Paul A Townsend,Andrey A Zamyatnin

doi:10.3390/ijms22094669

Abstract

Taken with the growing importance of cathepsin-mediated substrate proteolysis in tumor biology and progression, the focus and emphasis placed on therapeutic design and development is coming into fruition. Underpinning this approach is the invariable progression from the direction of fully characterizing cathepsin protease members and their substrate targets, towards targeting such an interaction with tangible therapeutics. The two groups of such substrates that have gained much attention over the years are the pro- and anti- apoptotic protein intermediates from the extrinsic and intrinsic signaling arms of the apoptosis pathway. As proteins that are central to determining cellular fate, some of them present themselves as very favorable candidates for therapeutic targeting. However, considering that both anti- and pro- apoptotic signaling intermediates have been reported to be downstream substrates for certain activated cathepsin proteases, therapeutic targeting approaches based on greater selectivity do need to be given greater consideration. Herein, we review the relationships shared by the cathepsin proteases and the Bcl-2 homology domain proteins, in the context of how the topical approach of adopting ‘BH3-mimetics’ can be explored further in modulating the relationship between the anti- and pro- apoptotic signaling intermediates from the intrinsic apoptosis pathway and their upstream cathepsin protease regulators. Based on this, we highlight important future considerations for improved therapeutic design.

Highlights

We discuss what potential exists in furthering such findings to incorporate the simultaneous co-modulation of cathepsin protease activity and its relationship shared with pro- and anti- apoptotic Bcl-2 protein members, with a view to highlighting how the therapeutic design of BH3-mimetic can be utilized for greater effect
We described the design of a novel cathepsin S-directed peptide inhibitor (CS-PEP1), based on a peptide sequence from the fungal papain protease inhibitor protein pit2, and which was identical to a sequence found within α-5 helix of the hydrophobic groove of anti-apoptotic Bcl-xL [79]
The anti-apoptotic Bcl-2 proteins have gained increasing importance for therapeutic targeting, from their abilities to drive cancer progression and the most extensive studies of which have described the targeting of Bcl-2, Bcl-xL, and Mcl-1 [81,82]

Summary

Introduction

BAX (or BAK) and the anti-apoptotic Bcl-2 protein, through the design of BH3-mimetics was unveiled to hold high therapeutic potential [45] While this has some clear-cut relevance in cancer development and progression (where deregulated apoptotic pathway intermediates commonly prevail [46]), a complex picture is, emerging about how the proposed therapeutic modulation of these pathways may be interconnected with other signaling cascades of relevance. We discuss what potential exists in furthering such findings to incorporate the simultaneous co-modulation of cathepsin protease activity and its relationship shared with pro- and anti- apoptotic Bcl-2 protein members, with a view to highlighting how the therapeutic design of BH3-mimetic can be utilized for greater effect

Pro-Apoptotic BAX and BAK as Substrate Proteins for Cathepsin Proteases

Anti-Apoptotic Bcl-2 Proteins as Substrates for the Cathepsin Proteases

BH3-Only Domain Proteins as Substrates for the Cathepsin Proteases

Cathepsin and the Bcl-2 Proteins

Findings

Future Directions