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Gene & Protein in Disease Targeting cathepsins during cancer development

altering the architecture of the ECM, 7,56,57 either as inactive predisposed to viral infections, whereas double-knockout
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zymogens or active mature proteases (Figure 2). The mice were embryonic lethal. 77,79 Studies on BOK-knockout
activation and cleavage of ECM components (Table 2) are mice have suggested that BOK expression is important
attributed to a decrease in extracellular pH. 9,58-62 Moreover, in a developmental context but redundant for initiating
secreted Cts as extracellular proteases can digest and shed developmental abnormalities. 80-82
specific immuno-regulatory chemokines, cytokines 63-66 , or Collectively, these findings highlight the biological
signaling receptor proteins, 60,67,68 which are responsible for importance of these proteins, particularly under conditions
tumor progression. Acidification of the ECM enhances the where they may be ablated through Cts overexpression.
redistribution of some Cts to the cell surface and increases This also reveals an important aspect of Cts research in
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cathepsin secretion under the acidic conditions prevalent the context of how unregulated Cts overexpression may
in the tumor microenvironment. 69 allow cancer cells to survive (or progress) in response
Under normal conditions, the autocatalytic activation to therapeutic treatments. 19,80 When combined with the
of molecular cysteine Cts requires mildly reducing and extracellular compartmentalization of Cts, two strategically
acidic conditions, 14,15 but it can also be activated by important aspects emerge for therapeutically targeting
glycosaminoglycans, as observed with Cts K activation. cancer cells based on their proliferation and metastatic
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Low pH conditions necessary for cysteine Cts activation status.
can diminish their enzymatic activity or activation Despite the significance of these research avenues, there
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capacity if exposed to neutral pH after secretion, similar have been only a limited number of published studies
to their inactive zymogenic pro-forms. A drop in pH can addressing or extending the ability of proapoptotic proteins
auto-activate Cts, as observed with pro-cathepsins B, K, L, to be targeted and digested by Cts. In this context, Cao et al.
and S, which cleave thyroglobulin in vitro, highlighting (2003) revealed that BAX cleavage by Calpain at Asp-33
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a pH-dependent mechanism by which extracellular Cts results in the formation of the cleavage product p18BAX,
can modulate ECM architecture. In addition, some ECM a step that could be blocked by cathepsin inhibition,
digestion products can enhance Cts expression and resulting in a 25 – 35% reduction in drug-induced
secretion by regulating autocrine or paracrine cellular apoptosis. Interestingly, the same group demonstrated that
signaling events. 71 inhibiting complete p18BAX degradation potentiated the
Collectively, these findings highlight the biological apoptosis of A-549, U-937, and K-562 cells by 25 – 40%.
significance of Cts expression and regulation in tumor These findings suggested the importance of p18BAX and
development, proliferation, cellular differentiation, its ability to enhance BAX-mediated apoptosis. Further
and metastatic dispersal under dynamic physiological evidence supporting the role of BAX Asp-33 emerged from
conditions. Importantly, such studies support the rationale studies on a BAX Asp-33-Ala mutation, which prevented
for Cts as potential diagnostic or prognostic biomarkers the binding of BID protein to BAX. 84,85
for specific cancers. 19 In a similar study, Droga-Mazovec et al. (2008)
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4. BH3-protein complexes are target reported that BAK cleavage in vitro was mediated by Cts B,
L, S, and K, whereas our group reported the in vitro cleavage
substrates for Cts of BAX by Cts S. Moreover, in our study, inhibition of Cts
4.1. Proapoptotic proteins as target substrates for Cts S by a novel inhibitor (CS-PEP1) had a stabilizing effect on

As proteins that induce MOMP, the importance of p21BAX steady-state protein levels. 86
apoptotic proteins BAX, BAK, and BOK in determining 4.2. Antiapoptotic proteins as target substrates for Cts
cell fate and disease progression has been supported by
findings from several model systems. For example, frame- As with proapoptotic BH3-proteins, antiapoptotic BH3-
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shift mutations in BAX have been linked to colon or proteins have also been examined for their ability to
lung cancers and T-cell acute lymphocytic leukemia, 73,74 be cleaved by Cts. Cleavage of these proteins would
whereas the loss of BAX expression potentiates mammary predictably result in greater levels of proapoptotic proteins,
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tumor development in mice. BAX deficiency also leads potentiating therapy-induced cancer cell death.
to abnormal B- and T-cell numbers, including defective Notable examples of overexpressed antiapoptotic
spermatogenesis, underscoring the link between Bcl-2 proteins that drive cancer progression include
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BAX expression and apoptosis in diverse physiological Bcl-2, Bcl-xL, and Mcl-1, some of which competitively
processes. Notably, despite the similar molecular roles of deplete BH3-only proapoptotic proteins. 87,88 In the case
BAX and BAK proteins, no defects were observed in BAK- of Bcl-2 overexpression, malignancies such as lymphoma,
deficient mice. However, both single-knockout mice were prostate cancer, and small cell lung cancer. 89-91 Similarly,
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Volume 4 Issue 3 (2025) 5 doi: 10.36922/gpd.4768