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

Abstract

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.

In vitro measurement of cell death with the annexin A5 affinity assay

“…Expression of PS relies on activated caspase 3 in CD95-induced apoptotic cell death, whereas cathepsin B activity is necessary for PS expression in tumor necrosis factor-α-induced caspase-independent cell death 8,9 . Several studies have shown that pathways exist that cause cell surface expression of PS by living cells in specific conditions.…”

Mechanistic insight into taxol-induced cell death

“…These modes of PCD are characterized by an essential activity of proteases other than caspases during the onset or execution phase of cell death. For example, cathepsins (Foghsgaard et al, 2001;Bidere et al, 2003;Broker et al, 2004), calpains (Karmakar et al, 2007;Pineiro et al, 2007) and yet uncharacterized proteases (de Bruin et al, 2003) were reported to play key roles in different cell death models.…”

Apoptosis caused by cathepsins does not require Bid signaling in an in vivo model of progressive myoclonus epilepsy (EPM1)

“…1,2 In addition to the traditional apoptotic process mediated by caspases, other proteases such as the cathepsin cysteine proteases have been shown to participate in apoptotic signaling. [3][4][5][6][7][8][9][10][11][12][13][14] Although cathepsins normally reside in the lysosome and carry out nonselective degradation of proteins, a strong case was made for the involvement of these proteases in apoptosis when it was shown that agents that disrupted lysosomes and caused cathepsins to redistribute to the cytoplasm inevitably resulted in apoptosis. 13,[15][16][17][18][19] Similarly, cathepsin inhibitor treatment blocked this apoptosis.…”