Cathepsin B Acts as a Dominant Execution Protease in Tumor Cell Apoptosis Induced by Tumor Necrosis Factor

By L. Foghsgaard, D. Wissing, D. Mauch, U. Lademann, L. Bastholm, M. Boes, F. Elling, Marcel Leist, M. Jäättelä. Journal of Cell Biology, 2001

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Death receptors can trigger cell demise dependent or independent of caspases. In WEHI-S fibrosarcoma cells, tumor necrosis factor (TNF) induced an increase in cytosolic cathepsin B activity followed by death with apoptotic features. Surprisingly, this process was enhanced by low, but effectively inhibiting, concentrations of pan-caspase inhibitors. Contrary to caspase inhibitors, a panel of pharmacological cathepsin B inhibitors, the endogenous cathepsin inhibitor cystatin A as well as antisense-mediated depletion of cathepsin B rescued WEHI-S cells from apoptosis triggered by TNF or TNF-related apoptosis-inducing ligand. Thus, cathepsin B can take over the role of the dominant execution protease in death receptor-induced apoptosis. The conservation of this alternative execution pathway was further examined in other tumor cell lines. Here, cathepsin B acted as an essential downstream mediator of TNF-triggered and caspase-initiated apoptosis cascade, whereas apoptosis of primary cells was only minimally dependent on cathepsin B. These data imply that cathepsin B, which is commonly overexpressed in human primary tumors, may have two opposing roles in malignancy, reducing it by its proapoptotic features and enhancing it by its known facilitation of invasion.

Subfields: Cancer Research, Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5301a7f2df5200e757b8eb0359ec1bf4f4ad7232

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Citations in the corpus

NF‐κB protects from the lysosomal pathway of cell death (2003, background): “The relationship between the lysosomal and caspase pathways of apoptosis is not fully elucidated and seems to depend on the nature of the apoptotic signal and cell type in question (Ferri and Kroemer, 2001; Foghsgaard et al., 2001).”
Lysosomes and autophagy in cell death control (2005, background): “One of the reasons for this delay is that methylketone peptide inhibitors (for example, zVAD-fluoromethylketone (fmk)) that are commonly used to assess the role of caspases in PCD also inhibit other cysteine proteases, including several lysosomal cathepsin”
Death by design: apoptosis, necrosis and autophagy. (2004, background): “However, this drug can inhibit cathepsins at the same concentrations at which caspases are inhibited and thus might affect lysosomal degradation and have additional non-specific effects on the cell [18].”
Caspase-independent cell death (2005, background): “Accordingly, caspase inhibitors have been shown to sensitize cells to apoptosis inducers in vitro”
Lysosomal membrane permeabilization in cell death (2008, background): “Caspases are activated upstream of LMP after TNF-a treatment of ME-180 cells but not after an identical treatment of WEHI-S cells, indicating that the relative hierarchical position of LMP and caspase activation depends on the cell type (Foghsgaard et al., 2001).”
Necrosis: a specific form of programmed cell death? (2003, background): “For instance, TNF-induced cell death of hepatocytes and tumor cells apparently requires lysosomal cysteine protease cathepsine B [143,144].”
Lysosomes in cell death (2004, background): “Indeed, misleading data have been generated from studies utilizing pharmacological inhibitors of caspases, which, at the concentrations generally used, are now known to inhibit also other proteases, including cathepsins (Faubion et al., 1999; Foghsgaard et al., 2001).”
Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. (2004, background): “While certain cathepsins have been shown to be involved in mediating apoptosis triggered by specific stimuli (e.g., TNF-induced apoptosis [Foghsgaard et al., 2001]), the pharmacological trials with JPMOEt indicate that cathepsins are not centrally involved in the acquired resistance to apoptosis…”
The lysosome: from waste bag to potential therapeutic target. (2013, background): “Cathepsin B induces typical apoptosis-associated changes, including chromatin condensation, DNA fragmentation, phosphatidylserine exposure, and plasma membrane blebbing (Vancompernolle et al., 1998; Foghsgaard et al., 2001).”