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Gene & Protein in Disease Targeting cathepsins during cancer development

The BH3 domain present within the α-helix 2 of Encouragingly, several high-efficacy antagonists have
proapoptotic Bcl-2 proteins is of therapeutic importance, emerged with promising clinical potential as single or
comprises approximately 15 amino acids, and binds to the combination therapeutics. Furthermore, based on recent
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hydrophobic pocket spanning α-helices 2 – 5 within the developments, the use of BH3-mimetics and their design
antiapoptotic proteins. As shown in Table 1, intracellular principles as potential cancer therapeutics followed by
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proapoptotic proteins are broadly negatively regulated clinical testing has shown success with the emergence of
by several antiapoptotic proteins, depending on their Bcl-xL mimetics, Mcl-1 inhibitors, SMAC-mimetics, and
relative abundance, subcellular compartmentalization, and cIAP inhibitors.
specific biochemical and physiological activation cues. Mechanistically, it is becoming clear that Cts are strongly
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These factors collectively define the extent to which BAK linked to proteolytically modulating key regulatory
and BAX proteins form the mitochondrial pore complex,
resulting in enlarged mitochondrial cristae, cytochrome c intermediates of the apoptotic pathway (Figure 2). When
release, DNA fragmentation, and cellular death. 30,31 considered alongside recent advancements in mimetic
(and inhibitor) technology, we offer a fresh perspective on
These mechanisms underlying the early activation of these therapeutics, emphasizing their potential to disrupt
apoptosis have been exploited for therapeutic development. key cathepsin-BH3 substrate cleavage as a new generation
Therapeutics have been targeted at the proapoptotic BH3 of dual-acting anticancer therapeutics. We highlighted
domain/antiapoptotic Bcl-2 protein hydrophobic pocket, the biochemical criteria that must be fulfilled by these
with an aim to enhance oligomerization of BAK (or BAX) therapeutics to favor elevated levels of active proapoptotic
and promote mitochondrial pore complex formation. Bcl-2 proteins, a central requirement for cancer cells
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to undergo apoptosis with greater efficacy in single- or
Table 1. Three main proapoptotic, antiapoptotic, and
sensitizer (Sen) subgroups of the Bcl‑2 protein family combination therapeutic regimens in the clinic.
that reside in the cytoplasm (C), mitochondrion (M),
endoplasmic reticulum (ER), or nucleus (N) and are 2. Cts expression and cancer invasiveness
regulated through their interactions with other subgroup Cts are a group of lysosomal proteases, among which Cts
proteins C, B, H, K, O, L, Z, and S have been broadly expressed and
most extensively studied. These findings are largely derived
Protein Apoptosis Location Protein partners
from expression profiling studies, revealing general
BAX Pro- C, M, N, and ER BAK, Bcl-2, Bcl-xL, Mcl-1,
BID, BIM, and NOXA and reproducible mechanisms for lysosomal research
BAK Pro- M BAX, Bcl-2, Bcl-xL, Mcl-1, (Figure 2), substrate cleavage, angiogenesis, tumor
and BID proliferation, metastasis, and ECM degradation. 34,35 Strong
Bcl-2 Anti- C, M, N, and ER BAX, BAK, Bcl-xL, BID, BIM, evidence linking Cts overexpression and invasiveness
BAD, PUMA, and NOXA stems from Cts A overexpression in malignant melanoma
samples and enhanced Cts B expression in invasive B16
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Bcl-xL Anti- M and C BAX, BAK, Bcl-2, BID, BIM
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BAD, and PUMA melanoma cells. Similarly, Cts D overexpression was
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Mcl-1 Anti- C, M, and N BAX, BAK, BID, BIM, PUMA, observed in breast cancer (BC) cells and in patients with
and NOXA enhanced interpulmonary metastases. 39
BID Pro-/Sen- C and M BAX, BAK, Bcl-2, Bcl-xL, and Consistently, Cts expression and tumor invasiveness
Mcl-1 have been linked using various approaches and in vitro
BIM Pro-/Sen- C and M BAX, Bcl-2, Bcl-xL, and Mcl-1 models, such as forced overexpression of Cts D, which
BAD Pro-/Sen- C and M Bcl-2 and Bcl-xL effectively increases fibroblast invasiveness and motility.
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PUMA Pro-/Sen- M Bcl-2, Bcl-xL, and Mcl-1, Upregulation of Cts X expression correlated with
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NOXA Pro-/Sen- C, M, and N BAX, Bcl-2, and Mcl-1, invasiveness, similar to the expression dependency
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SMAC Pro-/Sen- C and M xIAP1 of Cts H in glioblastoma cell line models. Other
Abbreviations: BAK: Bcl-2 antagonist/killer; Bcl-xL: B-cell examples include enhanced expression of Cts K, which
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lymphoma-extra large; BID: Bcl-2 interacting domain death agonist; potentiated breast tumor epithelial cell development,
BIM: Bcl-2 interacting mediator of cell death; BAX: Bcl-2-associated and Cts S knockout, which reduced the invasiveness of
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protein X; cIAP: Cellular inhibitor of apoptosis proteins; DIABLO: Direct pancreatic cancer cells. Elevated Cts B expression was
IAP binding protein with low PI; PUMA: p53-upregulated modulator correlated with advanced-stage tumor progression and
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of apoptosis; SMAC: Second mitochondria-derived activator of BC malignancy, whereas Cts L knockdown reduced BC
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caspases; NOXA: Phorbol-12-myristate-13-acetate-induced protein 1; 48,49
Mcl-1: Myeloid cell leukemia-1 protein; xIAP1: X-linked inhibitor of tumor growth (and invasiveness) and sensitized glioma
apoptosis proteins. cells to radiotherapy. 49
Volume 4 Issue 3 (2025) 3 doi: 10.36922/gpd.4768