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Gene & Protein in Disease Targeting cathepsins during cancer development

Bcl-xL overexpression can underpin tumor development, However, BIM deficiency causes: 1) hyperplasia, as seen
particularly under conditions of Bcl-2-directed therapeutic in c-myc transgenic mice developing B-cell leukemia;
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resistance. 92-94 By analogy, Mcl-1 gene amplifications have and 2) tumor outgrowth from p53- and E1A-transformed
been reported in lung and breast cancers, contributing mouse kidney-derived epithelial cells. Further studies
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similarly to cancer development as Bcl-2 and Bcl-xL are needed to determine which Cts family members can
expression. Collectively, overexpression of antiapoptotic target BIM for degradation.
proteins can give damaged cells a survival advantage, In summary, therapeutically targeting the Cts that
paving the way for the accumulation of additional genetic mediate BH3-only protein breakdown may hold significant
lesions that drive tumor progression. 95,96 therapeutic potential. However, very little has been

With regard to cathepsin-mediated cleavage, Droga- reported on how currently available anti-cathepsin agents
Mazovec et al. (2008) observed the digestion of the affect the activation of specific BH3-only proteins and how
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antiapoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 following this step influences the initiation of apoptosis in cells.
treatment of cell lines with the lysosomal agent LeuLeuOMe.
Moreover, Cts B, L, S, and K were shown to cleave Bcl-2, 5. Targeting BH3-proteins with BH3-
Bcl-xL, Mcl-1, and XIAP in vitro at pH 7.2. Some of these mimetics and inhibitors
findings were confirmed by our group, which demonstrated Focused on the cellular apoptotic functions of BAK
that Bcl-xL could be targeted by Cts S in vitro. Collectively, and BAX, many structure-based studies have shown a
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these studies highlight the potential of Cts to promote cell likelihood of disrupting the BAX-antiapoptotic protein
death by depleting antiapoptotic protein levels, emphasizing interaction site through BH3-mimetic design. The rationale
their relevance in future anticancer therapeutic strategies is aimed at enhancing BAX protein levels to induce MOMP
that involve Cts inhibition.
and apoptosis. Similarly, Mcl-1 inhibitors and SMAC-
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4.3. BH3-only domain proteins as target substrates mimetics have been designed and tested for their ability to
for Cts target additional key regulatory signaling pathways from
the intrinsic apoptosis pathway (Figure 1).
The two most characterized members of this group are the
BID and BIM proteins. 85,97,98 Normally, BID functions by Early studies identified novel therapeutics targeting
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linking death receptor pathway signaling with MOMP. 99,100 Bcl-2 proteins through natural compound screening,
Following cleavage by caspase-8 or caspase-3, BID while rational drug design, coupled with structural studies,
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drives BAX insertion into the mitochondrial outer has led to the growing family of BH3-mimetics. These are
membrane, 103 inducing BAX-dependent MOMP. effective by targeting the hydrophobic groove of Bcl-2. This
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Similarly, the relationship between Cts-derived BID step hinders BAX binding to Bcl-2, allowing enhanced
cleavage and subsequent activation of MOMP is strongly levels of monomeric BAX (or BAK) upon therapeutic
supported by mouse models. In these models, BID/tissue stimulation of cancer cells. 88,112 This rationale led to the
extracts failed to release mitochondrial cytochrome development of a small inhibitor targeting Bcl-2, Bcl-xL, and
c when treated with lysosomal extracts, suggesting a Bcl-w binding, called ABT-263 (Navitoclax). 87,113 Although
prerequisite role for cathepsin-mediated cleavage in BID it showed promise for treating B-cell malignancies
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protein activation. 105,106 Similar effects were observed upon in phase I-II clinical trials, its platelet-depleting effects
chemically induced lysosomal leakage of Cts and cathepsin hindered further use. 114-119 However, an ABT-263 derivative
inhibition. Using such robust approaches, Cts B, H, L, (Venetoclax) successfully treated patients with chronic
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S, and K have been reported to cleave BID at residues lymphocytic leukemia (CLL), refractory CLL, and acute
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Arg-65 or Arg-71. In our studies, Cts S cleaved purified myeloid leukemia (AML). 120-122 Although largely ineffective
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BID in vitro, and co-expression studies in mammalian against chemotherapeutic-resistant solid tumors, it was
cells demonstrated that this effect could be abrogated by useful in treating thrombocytopenia and was further
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co-expression of catalytically-null Cts S and BID. While developed into derivatives such as WEHI-539, A1155463,
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this might suggest a cellular prosurvival effect of BID and and A-1331852. 124-126 A-1331852 was unveiled as the first
Cts S co-expression, it must be understood in the context antagonist targeting Bcl-xL.
of Cts S generating a p21 BAX-derived p18 BAX protein In leveraging this strategic approach, Venetoclax (and
derivative. This p18-BAX is likely more potent as a MOMP ABT-737) 127,128 were found to be largely ineffective in
inducer than p21BAX. 83 targeting Mcl-1 in cancer, highlighting the excellent target
Functionally, the BIM Bcl-2 interacting mediator (BIM) protein specificity of these compounds. 129,130 These and
of cell death mediates the negative selection of B- and a number of emerging therapeutics are summarized in
T-cell precursors due to its role in cellular death signaling. Table 3, along with their target BH3 proteins.
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Volume 4 Issue 3 (2025) 6 doi: 10.36922/gpd.4768