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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.

Original publication

DOI

10.1158/0008-5472.CAN-04-1427

Type

Journal article

Journal

Cancer Res

Publication Date

01/08/2004

Volume

64

Pages

5301 - 5310

Keywords

Animals, Antineoplastic Agents, Apoptosis, Caspase 3, Caspase Inhibitors, Caspases, Cathepsin B, Cathepsin D, Cathepsin L, Cathepsins, Cell Transformation, Neoplastic, Cysteine Endopeptidases, Cytochromes c, Drug Resistance, Neoplasm, Embryo, Mammalian, Enzyme Activation, Enzyme Inhibitors, Fibroblasts, Genes, ras, Genes, src, Lysosomes, Mice, Mice, Inbred C57BL, Mice, Knockout, NIH 3T3 Cells, RNA Interference, Signal Transduction, Transfection, Tumor Necrosis Factor-alpha