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Sensitization to the Lysosomal Cell Death Pathway upon Immortalization and Transformation

Sensitization to the Lysosomal Cell Death Pathway upon Immortalization and Transformation

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Prüfsumme: MD5:71a976f29e9900647a69010789677e63

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} }

Gyrd-Hansen, Mads Felbor, Ute Fehrenbacher, Nicole Poulsen, Birgit Felbor, Ute First publ. in: Cancer Research 64 (2004), pp. 5301-5310 Weber, Ekkehard Weber, Ekkehard Jäättelä, Marja deposit-license Leist, Marcel Boes, Marianne Boes, Marianne Kallunki, Tuula 2011-03-24T17:31:13Z Gyrd-Hansen, Mads Poulsen, Birgit eng 2004 application/pdf Leist, Marcel Kallunki, Tuula Jäättelä, Marja Fehrenbacher, Nicole Sensitization to the Lysosomal Cell Death Pathway upon Immortalization and Transformation 2011-03-24T17:31:13Z 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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