Original Article

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

Correspondence to: Marja Jäättelä, Apoptosis Laboratory, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. Tel:45-35257318 Fax:45-35257721 E-mail:mhj{at}biobase.dk.

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.

Key Words: apoptosis, cancer, caspase independent, cathepsins, tumor necrosis factor

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• Yuan, X.-M., Li, W., Dalen, H., Lotem, J., Kama, R., Sachs, L., Brunk, U. T. (2002). Lysosomal destabilization in p53-induced apoptosis. Proc. Natl. Acad. Sci. USA 99: 6286-6291 [Abstract] [Full Text]  
• Nakayama, M., Ishidoh, K., Kayagaki, N., Kojima, Y., Yamaguchi, N., Nakano, H., Kominami, E., Okumura, K., Yagita, H. (2002). Multiple Pathways of TWEAK-Induced Cell Death. J. Immunol. 168: 734-743 [Abstract] [Full Text]  
• Abreu, M. T., Arnold, E. T., Chow, J. Y. C., Barrett, K. E. (2001). Phosphatidylinositol 3-Kinase-dependent Pathways Oppose Fas-induced Apoptosis and Limit Chloride Secretion in Human Intestinal Epithelial Cells. IMPLICATIONS FOR INFLAMMATORY DIARRHEAL STATES. J. Biol. Chem. 276: 47563-47574 [Abstract] [Full Text]  
• Guicciardi, M. E., Miyoshi, H., Bronk, S. F., Gores, G. J. (2001). Cathepsin B Knockout Mice Are Resistant to Tumor Necrosis Factor-{alpha}-Mediated Hepatocyte Apoptosis and Liver Injury : Implications for Therapeutic Applications. Am. J. Pathol. 159: 2045-2054 [Abstract] [Full Text]  
• Yuan, X.-M., Li, W., Dalen, H., Lotem, J., Kama, R., Sachs, L., Brunk, U. T. (2002). Lysosomal destabilization in p53-induced apoptosis. Proc. Natl. Acad. Sci. USA 99: 6286-6291 [Abstract] [Full Text]  

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