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J. Cell Biol. 153 (5): 999-1010

Copyright © 2001 by the Rockefeller University Press.

Original Article

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

Lasse Foghsgaarda, Dorte Wissinga, Daniel Mauchb, Ulrik Lademanna, Lone Bastholmc, Marianne Boesd, Folmer Ellingc, Marcel Leistb,e, , and Marja Jäätteläa

a Apoptosis Laboratory, Danish Cancer Society, Copenhagen, Denmark
b Department of Molecular Toxicology, University of Konstanz, Konstanz, Germany
c Institute of Molecular Pathology, University of Copenhagen, Copenhagen, Denmark
d Department of Pathology, Harvard Medical School, Boston, Massachusetts
e H. Lundbeck A/S, Valby, Denmark
Apoptosis Laboratory, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.45-3525772145-35257318


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.

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

The online version of this article contains supplemental material.

M. Leist and M. Jäättelä share senior authorship.

Abbreviations used in this paper: AFC, 7-amino-trifluoromethylcoumarin; ALLN, N-Acetyl-leu-Leu-Nle-CHO; anti-CD95, agonistic antibody against CD95; Boc-D-fmk, Boc-Asp-CH2F; DEVD-CHO, acetyl-Asp-Glu-Val-Asp-aldehyde; IETD-CHO, acetyl-Ile-Glu-Thr-Asp-aldehyde; lactacystine, clasto-lactacystin-β-lactone; LDH, lactate dehydrogenase; MEF, murine embryonic fibroblast; MTT, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide; NF-{kappa}B, nuclear factor {kappa}B; PS, phosphatidylserine; rhTNF, recombinant human TNF; rmTNF, recombinant murine TNF; TLCK, N-{alpha}-Tosyl-L-Lys-chloromethyl ketone; TNF, tumor necrosis factor; TNF-R, TNF receptor; TPCK, tosyl-L-Phe-chloromethyl ketone; TRAIL, TNF-related apoptosis-inducing ligand; zFA-fmk, z-Phe-Ala-CH2F; zFK-mbmk, z-Phe-Lys-2,4,6-trimethylbenzoyloxymethylketone; zVAD-fmk, z-Val-Ala-DL-Asp-CH2F; zVDVAD-fmk, z-Val-Asp(OMe)-Val-Ala-Asp(OMe)-CH2F.

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J. Nylandsted, M. Gyrd-Hansen, A. Danielewicz, N. Fehrenbacher, U. Lademann, M. Hoyer-Hansen, E. Weber, G. Multhoff, M. Rohde, and M. Jaattela (2004)
J. Exp. Med. 200, 425-435
   Abstract »    Full Text »    PDF »
Sensitization to the Lysosomal Cell Death Pathway upon Immortalization and Transformation.
N. Fehrenbacher, M. Gyrd-Hansen, B. Poulsen, U. Felbor, T. Kallunki, M. Boes, E. Weber, M. Leist, and M. Jaattela (2004)
Cancer Res. 64, 5301-5310
   Abstract »    Full Text »    PDF »
TNF-{alpha}-mediated lysosomal permeabilization is FAN and caspase 8/Bid dependent.
N. Werneburg, M. E. Guicciardi, X.-M. Yin, and G. J. Gores (2004)
Am J Physiol Gastrointest Liver Physiol 287, G436-G443
   Abstract »    Full Text »    PDF »
Down-regulation of Sphingosine Kinase-1 by DNA Damage: DEPENDENCE ON PROTEASES AND p53.
T. A. Taha, W. Osta, L. Kozhaya, J. Bielawski, K. R. Johnson, W. E. Gillanders, G. S. Dbaibo, Y. A. Hannun, and L. M. Obeid (2004)
J. Biol. Chem. 279, 20546-20554
   Abstract »    Full Text »    PDF »
Nuclear Factor-{kappa}B Mediates Up-Regulation of Cathepsin B by Doxorubicin in Tumor Cells.
S. Bien, C. A. Ritter, M. Gratz, B. Sperker, J. Sonnemann, J. F. Beck, and H. K. Kroemer (2004)
Mol. Pharmacol. 65, 1092-1102
   Abstract »    Full Text »    PDF »
Cathepsin-Dependent Apoptosis Triggered by Supraoptimal Activation of T Lymphocytes: A Possible Mechanism of High Dose Tolerance.
M.-C. Michallet, F. Saltel, M. Flacher, J.-P. Revillard, and L. Genestier (2004)
J. Immunol. 172, 5405-5414
   Abstract »    Full Text »    PDF »
Induction of endoplasmic reticulum stress by ellipticine plant alkaloids.
M. Hagg, M. Berndtsson, A. Mandic, R. Zhou, M. C. Shoshan, and S. Linder (2004)
Mol. Cancer Ther. 3, 489-497
   Abstract »    Full Text »    PDF »
Differential Susceptibilities of Murine Hepatoma 1c1c7 and Tao Cells to the Lysosomal Photosensitizer NPe6: Influence of Aryl Hydrocarbon Receptor on Lysosomal Fragility and Protease Contents.
J. A. Caruso, P. A. Mathieu, A. Joiakim, B. Leeson, D. Kessel, B. F. Sloane, and J. J. Reiners Jr. (2004)
Mol. Pharmacol. 65, 1016-1028
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Xenopus Death Receptor-M1 and -M2, New Members of the Tumor Necrosis Factor Receptor Superfamily, Trigger Apoptotic Signaling by Differential Mechanisms.
K. Tamura, T. Noyama, Y.-h. Ishizawa, N. Takamatsu, T. Shiba, and M. Ito (2004)
J. Biol. Chem. 279, 7629-7635
   Abstract »    Full Text »    PDF »
Selective Disruption of Lysosomes in HeLa Cells Triggers Apoptosis Mediated by Cleavage of Bid by Multiple Papain-like Lysosomal Cathepsins.
T. Cirman, K. Oresic, G. D. Mazovec, V. Turk, J. C. Reed, R. M. Myers, G. S. Salvesen, and B. Turk (2004)
J. Biol. Chem. 279, 3578-3587
   Abstract »    Full Text »    PDF »
Cathepsin B Mediates Caspase-Independent Cell Death Induced by Microtubule Stabilizing Agents in Non-Small Cell Lung Cancer Cells.
L. E. Broker, C. Huisman, S. W. Span, J. A. Rodriguez, F. A. E. Kruyt, and G. Giaccone (2004)
Cancer Res. 64, 27-30
   Abstract »    Full Text »    PDF »
Cathepsin-B-dependent apoptosis triggered by antithymocyte globulins: a novel mechanism of T-cell depletion.
M.-C. Michallet, F. Saltel, X. Preville, M. Flacher, J.-P. Revillard, and L. Genestier (2003)
Blood 102, 3719-3726
   Abstract »    Full Text »    PDF »
Diarylurea Compounds Inhibit Caspase Activation by Preventing the Formation of the Active 700-Kilodalton Apoptosome Complex.
U. Lademann, K. Cain, M. Gyrd-Hansen, D. Brown, D. Peters, and M. Jaattela (2003)
Mol. Cell. Biol. 23, 7829-7837
   Abstract »    Full Text »    PDF »
Alternative Programs of Cell Death in Developing Retinal Tissue.
C. A. Guimaraes, M. Benchimol, G. P. Amarante-Mendes, and R. Linden (2003)
J. Biol. Chem. 278, 41938-41946
   Abstract »    Full Text »    PDF »
NF-{kappa}B protects from the lysosomal pathway of cell death.
N. Liu, S. M. Raja, F. Zazzeroni, S. S. Metkar, R. Shah, M. Zhang, Y. Wang, D. Bromme, W. A. Russin, J. C. Lee, et al. (2003)
EMBO J. 22, 5313-5322
   Abstract »    Full Text »    PDF »
Cathepsin D Triggers Bax Activation, Resulting in Selective Apoptosis-inducing Factor (AIF) Relocation in T Lymphocytes Entering the Early Commitment Phase to Apoptosis.
N. Bidere, H. K. Lorenzo, S. Carmona, M. Laforge, F. Harper, C. Dumont, and A. Senik (2003)
J. Biol. Chem. 278, 31401-31411
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The Tumor Suppressor cybL, a Component of the Respiratory Chain, Mediates Apoptosis Induction.
T. Albayrak, V. Scherhammer, N. Schoenfeld, E. Braziulis, T. Mund, M. K.A. Bauer, I. E. Scheffler, and S. Grimm (2003)
Mol. Biol. Cell 14, 3082-3096
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Overexpression of Legumain in Tumors Is Significant for Invasion/Metastasis and a Candidate Enzymatic Target for Prodrug Therapy.
C. Liu, C. Sun, H. Huang, K. Janda, and T. Edgington (2003)
Cancer Res. 63, 2957-2964
   Abstract »    Full Text »    PDF »
Inhibition of Phosphatidylinositol 3-Kinase Sensitizes Vascular Endothelial Cells to Cytokine-initiated Cathepsin-dependent Apoptosis.
L. A. Madge, J.-H. Li, J. Choi, and J. S. Pober (2003)
J. Biol. Chem. 278, 21295-21306
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Lysosomal Membrane Permeabilization Induces Cell Death in a Mitochondrion-dependent Fashion.
P. Boya, K. Andreau, D. Poncet, N. Zamzami, J.-L. Perfettini, D. Metivier, D. M. Ojcius, M. Jaattela, and G. Kroemer (2003)
J. Exp. Med. 197, 1323-1334
   Abstract »    Full Text »    PDF »

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