Cathepsin B: Multiple roles in cancer

Abstract

Proteases, including intracellular proteases, play roles at many different stages of malignant progression. Our focus here is cathepsin B, a lysosomal cysteine cathepsin. High levels of cathepsin B are found in a wide variety of human cancers, levels that often induce secretion and association of cathepsin B with the tumor cell membrane. In experimental models, such as transgenic models of murine pancreatic and mammary carcinomas, causal roles for cathepsin B have been demonstrated in initiation, growth/tumor cell proliferation, angiogenesis, invasion, and metastasis. Tumor growth in transgenic models is promoted by cathepsin B in tumor-associated cells, for example, tumor-associated macrophages, as well as in tumor cells. In transgenic models, the absence of cathepsin B has been associated with enhanced apoptosis, yet cathepsin B also has been shown to contribute to apoptosis. Cathepsin B is part of a proteolytic pathway identified in xenograft models of human glioma; targeting only cathepsin B in these tumors is less effective than targeting cathepsin B in combination with other proteases or protease receptors. Understanding the mechanisms responsible for increased expression of cathepsin B in tumors and association of cathepsin B with tumor cell membranes is needed to determine whether targeting cathepsin B could be of therapeutic benefit.

The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers

“…Proteases, like cathepsin B, also reside in the interstitium of tumors. They are highly expressed in a wide variety of tumors, including breast cancer tumors, and secreted by malignant cells (18,19,32). Extracellular cleavage of vc-seco-DUBA may therefore induce a bystander effect where not only the HER2-targeted tumor cell is killed, but also neighboring cells.…”

“…Proteases, like cathepsin B, are highly expressed in a wide variety of tumors, including breast cancer tumors, and can also be active extracellularly through secretion by malignant cells (18,19). The sensitivity of SYD985 and T-DM1 to cathepsin B cleavage was evaluated at pH 5 to mimic the acidic milieu in lysosomes and at pH 6, 6.5, and 7 to mimic pH in endosomes and tumor environment.…”

SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody–Drug Conjugate, Shows Antitumor Activity in Uterine Serous Carcinoma with HER2/Neu Expression

“…Importantly, our preclinical data with SYD985 clearly demonstrate that PI3K-mutated/T-resistant USC primary cell lines may be highly sensitive to this novel ADC and that SYD985 may be significantly more effective than T-DM1 in inducing bystander killing of low/negative HER2/ neu-expressing USC cells admixed with HER2/neu-positive tumors. In this regard, proteases like cathepsin B are expressed in a wide variety of human tumors including USC and are released by malignant cells (32). Cleavage of duocarmycine from its linker may therefore take place in USC not only within HER2/neu overexpressing tumor cells after antibody internalization (16,17) but also extracellularly within the tumor microenvironment, inducing a potent bystander effect.…”

Peptide-mediated core/satellite/shell multifunctional nanovehicles for precise imaging of cathepsin B activity and dual-enzyme controlled drug release

“…1 The abnormal expression of certain proteases is closely related to numerous human pathologies, including arthritis, 2 neurodegenerative disorders, 3 inflammatory processes, 4 cardiovascular diseases 5 and cancers. 6 Therefore, the development of chemical tools for in situ imaging of protease activity has gained considerable interest in recent years. A series of peptide-based molecular probes (PMPs) containing a signal donor and acceptor pair have been developed, [7][8][9][10] which translate enzymatic cleavage into detectable signals and provide promising noninvasive means to study cellular activities at the molecular level.…”

“…The system can be specifically disassembled by Cat B, a lysosomal cysteine protease overexpressed in a wide variety of human cancers. 6,25 The GNCs were shown to quench the fluorescence of FHMSNs by nanometal surface energy transfer (NSET). Then, hyaluronic acid (HA) molecules were assembled on the surface via peptide 2 (Pep2), which specifically binds to HA with a dissociation constant of 10 − 7 , 26 and HA then served as a shell that protected against nonspecific enzyme cleavage and an efficient target ligand for recognizing the CD44 and RHAMM receptors, which are overexpressed on the surface of cancer cells.…”