Tumor necrosis factor α sensitizes malignant cells to chemotherapeutic drugs via the mitochondrial apoptosis pathway independently of caspase-8 and NF-κB

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Abstract
The Hodgkin cell line HD-MyZ is resistant to apoptosis induced by tumor necrosis factor α (TNFα). In the present work, we show that pretreatment with TNFα sensitized the cells to apoptosis induced by antineoplastic agents and ceramide. TNFα 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 TNFα. Furthermore, exogenous ceramide, a mediator of TNFα signaling, could not substitute for TNFα in sensitization to drug-induced apoptosis. In contrast, we observed mitochondrial changes following cotreatment of cells with TNFα and drugs. Mitochondrial permeability transition, cytochrome c release and subsequent processing of caspase-9 preceded the onset of apoptosis, and were enhanced by TNFα pretreatment. Interestingly, although transcription factor NF-κB protected HD-MyZ cells from drug-induced apoptosis, TNFα-mediated sensitization was independent of NF-κB, since overexpressing a dominant-negative IκB mutant did not alter the TNFα effect. Sensitization for drug-induced apoptosis by TNFα was abrogated by Bcl-xL. Thus, the sensitizing effect of TNFα 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-κB signaling. Therefore, sensitization by TNFα is mediated at least in part through different pathways, as reported for TRAIL. There, sensitization occurs through a FADD/caspase-8-dependent mechanism. Regarding TNFα, the sensitizing effect was also observed in myeloid leukemia cells. Therefore, TNFα or alternate molecules activating its pathways might be useful as sensitizers for chemotherapy in hematological malignancies.

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