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Gene & Protein in Disease Targeting cathepsins during cancer development

cathepsin overexpression, reduced intracellular pH, or pathway. Of particular importance are the two main
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perturbations in the intracellular oxidation state of cells, subgroups: proapoptotic and antiapoptotic proteins,
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some Cts become cytoplasmically localized or are secreted which can be classified into three groups based on the
into the ECM. As a novel regulatory step, they can be similarities of their Bcl-2 homology (BH) domains. 24,25
5-8
expressed as protein isoforms derived from alternative The proapoptotic proteins Bcl-2 ovarian killer (BOK),
transcriptional promoters and mRNA splicing events, Bcl-2 antagonist/killer (BAK), and Bcl-2-associated
which can localize them to the mitochondria or nuclei to protein X (BAX) contain four BH1-4 domains and directly
regulate cellular proliferation and fate. In general, cysteine promote mitochondrial outer membrane permeabilization
8
Cts activation occurs under low pH conditions, as reported (MOMP). 26,27 The antiapoptotic proteins B-cell lymphoma-
for Cts B, K, and L. Taken together, these reports reveal extra large (Bcl-xL), B-cell lymphoma 2 (Bcl-2), and Mcl-1
9,10
important cues that determine the spatio-temporal nature also contain four BH1-4 domains and suppress MOMP by
of Cts expression, some of which originate from the directly binding BAX or BAK. The proapoptotic BH3-only
metabolic reprogramming of cells during the development (or “sensitizer”) proteins include Bcl-2 interacting domain
of specific diseases. 9 death agonist (BID), Bcl-2 antagonist of cell death (BAD),
From a clinical perspective, growing evidence suggests Bcl-2 interacting mediator of cell death (BIM), p53-
that specific Cts have significant potential as therapeutic upregulated modulator of apoptosis (PUMA), and NOXA.
targets, mainly due to their overexpression (or secretion) Concomitantly, therapeutically targeting such pathway
in certain cancer types, macrophages, and fibroblasts. The intermediates has led to the development of several
regulatory role of Cts among these cell types is emerging as promising clinical agents, including BH3-mimetics, Mcl-1
inhibitors, and SMAC-mimetics (Figure 1).
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complex and dynamic, as recently reviewed in the context
of gastric cancer progression. 11
Cts are involved in cancer progression with heightened
activation under low pH conditions, which prevail in
hypoxic environments where some tumor types can thrive.
7
Overexpressed and secreted cysteine Cts B, L, D, and S show
great potential as therapeutic targets for a broad spectrum
of cancers. More specifically, overexpressed intracellular
4
Cts can target key substrate proteins from the apoptotic
pathway, such as BAX and BID, 12,13 particularly under low
pH conditions. 9,14,15 Consequently, a diverse range of anti-
cathepsin targeting agents have been developed, including
small molecule inhibitors and peptide therapeutics. Their
clinical potential has been further explored through
activity-based probes, photosensitization activity-
based probes, and prodrugs. 16-18 Broadly, these targeting
approaches are based on established reports showing that, Figure 1. The central role and targeting of Bcl-2 homology 3 (BH3) proteins
under normal conditions, intracellular Cts are susceptible in the regulation of mitochondrial outer membrane permeabilization
to cystatin protein-mediated inhibition, as clearly (MOMP) and apoptosis. The antiapoptotic proteins B-cell lymphoma 2
demonstrated by Cts B. 19-21 (Bcl-2), Bcl-xL, and Mcl-1 (solid green box) negatively regulate Bcl-2-
associated X protein (BAX) (solid orange box)-mediated apoptotic effects
Based on the intrinsic connections between Cts, their by controlling cytochrome c release (solid yellow box and circles) and
overexpression, cytoplasmic localization, and ability to caspase protein activation. The blue solid boxes indicate mitochondrial
target the proteolysis of certain members of the pro- and SMAC/DIABLO, NOXA, and p53-upregulated modulator of apoptosis
(PUMA), which bind to the inhibitor of apoptosis proteins (solid green
antiapoptotic BH3 family of proteins, a complex picture box, IAPs) and whose interactions can be inhibited by SMAC-mimetics
is emerging of how cathepsins may modulate cell fate. (red box). Protein–protein interactions targeted by BH3-mimetics
This raises questions about the extent to which they and Mcl-1 inhibitors are also highlighted in red boxes. Adapted from
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are good candidates for future therapeutic design and Townsend et al. Copyright © 2021 Authors.
Abbreviations: BAK: Bcl-2 antagonist/killer; Bcl-xL: B-cell lymphoma-
targeting. extra large; BID: Bcl-2 interacting domain death agonist; BAX: Bcl-
It is well established that the expression of the Bcl-2 2-associated protein X; DIABLO: Direct IAP binding protein with
family of proteins can determine the sensitivity of low PI; IAP: Inhibitor of apoptosis proteins; PUMA: p53-upregulated
modulator of apoptosis; SMAC: Second mitochondria-derived activator
therapeutically treated cancer cells to undergo cell death of caspases; NOXA: Phorbol-12-myristate-13-acetate-induced protein 1;
through the central regulation of the intrinsic apoptosis Mcl-1: Myeloid cell leukemia-1 protein.

Volume 4 Issue 3 (2025) 2 doi: 10.36922/gpd.4768