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Cysteine cathepsins: From structure, function and regulation to new frontiers☆
  • V. Turk, V. Stoka, +4 authors D. Turk
  • Biology, Medicine
    Biochimica et Biophysica Acta (BBA) - Proteins…
  • 12 October 2011
The view of cysteine cathepsins as lysosomal proteases is changing as there is now clear evidence of their localization in other cellular compartments, and some of the remarkable advances that have taken place in the past decade are presented.
Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer.
It is shown that mouse mammary tumor virus-polyoma middle T antigen (PyMT) transgenic mice deficient for the cysteine protease cathepsin B (CTSB) exhibited a significantly delayed onset and reduced growth rate of mammary cancers compared with wild-type PyMT mice.
Emerging roles of cysteine cathepsins in disease and their potential as drug targets.
The current view on cathepsins as an emerging group of targets for several diseases and the development ofCathepsin K and S inhibitors for treatment of osteoporosis and various immune disorders are discussed.
Tumor-Specific Activation of an EGFR-Targeting Probody Enhances Therapeutic Index
The development of a Probody that targets epidermal growth factor receptor (EGFR) only in the presence of tumor is reported, with markedly improved safety and increased half-life in nonhuman primates, enabling it to be dosed safely at much higher levels than cetuximab.
Ferri-liposomes as an MRI-visible drug-delivery system for targeting tumours and their microenvironment.
The ferri-liposomes were used to deliver a cathepsin protease inhibitor to a mammary tumour and its microenvironment in a mouse, which substantially reduced the size of the tumour compared with systemic delivery of the same drug.
Inhibition of papain-like cysteine proteases and legumain by caspase-specific inhibitors: when reaction mechanism is more important than specificity
The results suggest that data based on the use of these inhibitors should be taken with caution and that other proteases may be implicated in the processes previously ascribed solely to caspases.
Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice
It is concluded that the double deficiency of Ctsb and Ctsz exerts significant synergistic anticancer effects, whereas the single deficiencies demonstrate at least partial reciprocal compensation.
Dual contrasting roles of cysteine cathepsins in cancer progression: apoptosis versus tumour invasion.
An insight is provided into the mechanisms by which cysteine cathepsins modulate apoptosis and/or participate in tumour invasion, and the impact of these enzymes on both tumour progression and development of potential strategies for cancer treatment is evaluated.
Autocatalytic processing of procathepsin B is triggered by proenzyme activity
A model for autocatalytic activation of cysteine cathepsins is proposed, involving propeptide dissociation from the active‐site cleft as the first step during zymogen activation.
Reduced tumour cell proliferation and delayed development of high-grade mammary carcinomas in cathepsin B-deficient mice
An in vivo role for Ctsb is indicated in promoting cellular anaplasia in mammary cancers and proliferation in lung metastases and resistance to apoptosis induction by the lysosomotropic agent Leu-Leu-OMe.