Type of Publication: | Journal article |
URI (citable link): | http://nbn-resolving.de/urn:nbn:de:bsz:352-opus-81503 |
Author: | Fehrenbacher, Nicole; Gyrd-Hansen, Mads; Poulsen, Birgit; Felbor, Ute; Kallunki, Tuula; Boes, Marianne; Weber, Ekkehard; Leist, Marcel; Jäättelä, Marja |
Year of publication: | 2004 |
Published in: | Cancer Research ; 64 (2004), 15. - pp. 5301-5310. - ISSN 0008-5472. - eISSN 1538-7445 |
Pubmed ID: | 15289336 |
DOI (citable link): | https://dx.doi.org/10.1158/0008-5472.CAN-04-1427 |
Summary: |
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.
|
Subject (DDC): | 570 Biosciences, Biology |
Link to License: | In Copyright |
FEHRENBACHER, Nicole, Mads GYRD-HANSEN, Birgit POULSEN, Ute FELBOR, Tuula KALLUNKI, Marianne BOES, Ekkehard WEBER, Marcel LEIST, Marja JÄÄTTELÄ, 2004. Sensitization to the Lysosomal Cell Death Pathway upon Immortalization and Transformation. In: Cancer Research. 64(15), pp. 5301-5310. ISSN 0008-5472. eISSN 1538-7445. Available under: doi: 10.1158/0008-5472.CAN-04-1427
@article{Fehrenbacher2004Sensi-7064, title={Sensitization to the Lysosomal Cell Death Pathway upon Immortalization and Transformation}, year={2004}, doi={10.1158/0008-5472.CAN-04-1427}, number={15}, volume={64}, issn={0008-5472}, journal={Cancer Research}, pages={5301--5310}, author={Fehrenbacher, Nicole and Gyrd-Hansen, Mads and Poulsen, Birgit and Felbor, Ute and Kallunki, Tuula and Boes, Marianne and Weber, Ekkehard and Leist, Marcel and Jäättelä, Marja} }
nicole_cr04.pdf | 611 |