Cathepsin B acts as a dominant execution protease in tumor cell apoptosis induced by tumor necrosis factor

Death receptors can trigger cell demise dependent or independent of caspase s, In WEHI-S fibrosarcoma cells, tumor necrosis factor (TNF) induced an inc rease in cytosolic cathepsin B activity followed by death with apoptotic fe atures, Surprisingly, this process was enhanced by low, but effectively inh ibiting, concentrations of pan-caspase inhibitors. Contrary to caspase inhi bitors, a panel of pharmacological cathepsin B inhibitors, the endogenous c athepsin inhibitor cystatin A as well as antisense-mediated depletion of ca thepsin B rescued WEHI-S cells from apoptosis triggered by TNF or TNF-relat ed apoptosis-inducing ligand. Thus, cathepsin B can take over the role of t he dominant execution protease in death receptor-induced apoptosis. The con servation of this alternative execution pathway was further examined in oth er tumor cell lines. Here, cathepsin B acted as an essential downstream med iator of TNF-triggered and caspase-initiated apoptosis cascade, whereas apo ptosis of primary cells was only minimally dependent on cathepsin B, These data imply that cathepsin B, which is commonly overexpressed in human prima ry tumors, may have two opposing roles in malignancy reducing it by its pro apoptotic features and enhancing it by its known facilitation of invasion.