Sensitization to the Lysosomal Cell Death Pathway upon Immortalization and Transformation

Fehrenbacher, Nicole; Gyrd-Hansen, Mads; Poulsen, Birgit; Felbor, Ute; Kallunki, Tuula; Boes, Marianne; Weber, Ekkehard; Leist, Marcel; Jäättelä, Marja

Sensitization to the Lysosomal Cell Death Pathway upon Immortalization and Transformation

Dateien

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Datum

2004

Autor:innen

Fehrenbacher, Nicole

Gyrd-Hansen, Mads

Poulsen, Birgit

Felbor, Ute

Kallunki, Tuula

Boes, Marianne

Weber, Ekkehard

Leist, Marcel

Jäättelä, Marja

Open Access-Veröffentlichung

Open Access Green

Sammlungen

Biologie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

Cancer Research. 2004, 64(15), pp. 5301-5310. ISSN 0008-5472. eISSN 1538-7445. Available under: doi: 10.1158/0008-5472.CAN-04-1427

Zusammenfassung

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.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Zitieren

ISO 690

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. 2004, 64(15), pp. 5301-5310. ISSN 0008-5472. eISSN 1538-7445. Available under: doi: 10.1158/0008-5472.CAN-04-1427

BibTex

@article{Fehrenbacher2004Sensi-7064,
  year={2004},
  doi={10.1158/0008-5472.CAN-04-1427},
  title={Sensitization to the Lysosomal Cell Death Pathway upon Immortalization and Transformation},
  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}
}

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Universitätsbibliographie

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