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Tumor necrosis factor alpha sensitizes malignant cells to chemotherapeutic drugs via the mitochondrial apoptosis pathway independently of caspase-8 and NF-kappaB
- Source :
- Oncogene. 23(40)
- Publication Year :
- 2004
-
Abstract
- The Hodgkin cell line HD-MyZ is resistant to apoptosis induced by tumor necrosis factor alpha (TNFalpha). In the present work, we show that pretreatment with TNFalpha sensitized the cells to apoptosis induced by antineoplastic agents and ceramide. TNFalpha pretreatment resulted in enhanced cleavage and activity of caspase-3 upon addition of etoposide, epirubicin or ceramide. No caspase-8 activation was detectable, although caspase-8 could be activated in cell-free extracts. Inhibition of caspase-8 by z-IETD-fmk did not block the sensitizing effect of TNFalpha. Furthermore, exogenous ceramide, a mediator of TNFalpha signaling, could not substitute for TNFalpha in sensitization to drug-induced apoptosis. In contrast, we observed mitochondrial changes following cotreatment of cells with TNFalpha and drugs. Mitochondrial permeability transition, cytochrome c release and subsequent processing of caspase-9 preceded the onset of apoptosis, and were enhanced by TNFalpha pretreatment. Interestingly, although transcription factor NF-kappaB protected HD-MyZ cells from drug-induced apoptosis, TNFalpha-mediated sensitization was independent of NF-kappaB, since overexpressing a dominant-negative IkappaB mutant did not alter the TNFalpha effect. Sensitization for drug-induced apoptosis by TNFalpha was abrogated by Bcl-x(L). Thus, the sensitizing effect of TNFalpha is mediated by the mitochondrial pathway and involves processing of caspase-2, -3 and -9, but appears to be independent of caspase-8 processing, Bid cleavage and NF-kappaB signaling. Therefore, sensitization by TNFalpha is mediated at least in part through different pathways, as reported for TRAIL. There, sensitization occurs through a FADD/caspase-8-dependent mechanism. Regarding TNFalpha, the sensitizing effect was also observed in myeloid leukemia cells. Therefore, TNFalpha or alternate molecules activating its pathways might be useful as sensitizers for chemotherapy in hematological malignancies.
- Subjects :
- Adult
Cancer Research
Ceramide
medicine.medical_specialty
medicine.medical_treatment
bcl-X Protein
Antineoplastic Agents
Apoptosis
Biology
Caspase 8
Ceramides
Membrane Potentials
chemistry.chemical_compound
Internal medicine
Cell Line, Tumor
Genetics
medicine
Humans
FADD
Molecular Biology
Sensitization
Epirubicin
Etoposide
Cell Death
Tumor Necrosis Factor-alpha
NF-kappa B
Intracellular Membranes
Blotting, Northern
Hodgkin Disease
Mitochondria
Sphingomyelins
medicine.anatomical_structure
Cytokine
Endocrinology
chemistry
Mitochondrial permeability transition pore
Proto-Oncogene Proteins c-bcl-2
Drug Resistance, Neoplasm
Leukemia, Myeloid
Caspases
biology.protein
Cancer research
Tumor necrosis factor alpha
Subjects
Details
- ISSN :
- 09509232
- Volume :
- 23
- Issue :
- 40
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....b2f7a4b456581fbe6ac39955018353ad