| Sensitization to the lysosomal cell death pathway upon immortalization and transformation. | |
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MedLine Citation:
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PMID: 15289336 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Tumorigenesis is associated with several changes that alter the cellular susceptibility to programmed cell death. Here, we show that immortalization and transformation sensitize cells in particular to the cysteine cathepsin-mediated lysosomal death pathway. Spontaneous immortalization increased the susceptibility of wild-type murine embryonic fibroblasts (MEFs) to tumor necrosis factor (TNF)-mediated cytotoxicity >1000-fold, whereas immortalized MEFs deficient for lysosomal cysteine protease cathepsin B (CathB) retained the resistant phenotype of primary cells. This effect was specific for cysteine cathepsins, because also lack of cathepsin L (a lysosomal cysteine protease), but not that of cathepsin D (a lysosomal aspartyl protease) or caspase-3 (the major executioner protease in classic apoptosis) inhibited the immortalization-associated sensitization of MEFs to TNF. Oncogene-driven transformation of immortalized MEFs was associated with a dramatic increase in cathepsin expression and additional sensitization to the cysteine cathepsin-mediated death pathway. Importantly, exogenous expression of CathB partially reversed the resistant phenotype of immortalized CathB-deficient MEFs, and the inhibition of CathB activity by pharmacological inhibitors or RNA interference attenuated TNF-induced cytotoxicity in immortalized and transformed wild-type cells. Thus, tumorigenesis-associated changes in lysosomes may counteract cancer progression and enhance therapeutic responses by sensitizing cells to programmed cell death. |
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Authors:
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Nicole Fehrenbacher; Mads Gyrd-Hansen; Birgit Poulsen; Ute Felbor; Tuula Kallunki; Marianne Boes; Ekkehard Weber; Marcel Leist; Marja Jäättelä |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Cancer research Volume: 64 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 2004 Aug |
Date Detail:
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Created Date: 2004-08-03 Completed Date: 2004-09-09 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 5301-10 Citation Subset: IM |
Affiliation:
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Apoptosis Department, Institute for Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / pharmacology Apoptosis / drug effects* Caspase 3 Caspases / antagonists & inhibitors, genetics, physiology Cathepsin B / antagonists & inhibitors, genetics, physiology Cathepsin D / antagonists & inhibitors, genetics, physiology Cathepsin L Cathepsins / antagonists & inhibitors, genetics, physiology Cell Transformation, Neoplastic* Cysteine Endopeptidases Cytochromes c / metabolism Drug Resistance, Neoplasm* Embryo, Mammalian / cytology*, drug effects, metabolism Enzyme Activation Enzyme Inhibitors / pharmacology Fibroblasts / cytology, drug effects*, enzymology Genes, ras / physiology Genes, src / physiology Lysosomes / enzymology* Mice Mice, Inbred C57BL Mice, Knockout NIH 3T3 Cells RNA Interference Signal Transduction Transfection Tumor Necrosis Factor-alpha / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Enzyme Inhibitors; 0/Tumor Necrosis Factor-alpha; 9007-43-6/Cytochromes c; EC 3.4.-/Cathepsins; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.22.1/Cathepsin B; EC 3.4.22.15/Cathepsin L; EC 3.4.22.15/Ctsl protein, mouse; EC 3.4.23.5/Cathepsin D |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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