Resistance to CD95/Fas‐induced and ceramide‐mediated apoptosis of human melanoma cells is caused by a defective mitochondrial cytochrome <i>c</i> release

Raisova, Monika; Bektas, Meryem; Wieder, Thomas; Daniel, Peter T.; Eberle, Jürgen; Orfanos, Constantin E.; Geilen, Christoph C.

doi:10.1016/s0014-5793(00)01491-5

Cited by 89 publications

(65 citation statements)

References 39 publications

(37 reference statements)

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“…Casp: caspase assumption was substantiated by measurements showing that calicheamicin-induced mitochondrial activation was accompanied by cytochrome c release into the cytosol and cleavage of caspase-9 that preceded processing of procaspase-3 to the active 17 kDa subunit. Both cytochrome c release and procaspase-9 processing are generally accepted as essential parts of mitochondrial signalling and execution (Li et al, 1997;Liu et al, 1996;Raisova et al, 2000;von Haefen et al, 2002). This is well in line with our finding that calicheamicin-induced cell death can be inhibited by Bcl-2 and Bcl-x L , as these proteins are key regulators of mitochondrial cytochrome c release.…”

Section: Discussionsupporting

confidence: 90%

Induction of apoptosis by enediyne antibiotic calicheamicin ϑII proceeds through a caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner

et al. 2003

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Calicheamicin 0II is a member of the enediyne class of antitumor antibiotics that bind to DNA and induce apoptosis. These compounds differ, however, from conventional anticancer drugs as they bind in a sequencespecific manner noncovalently to DNA and cause sequence-selective oxidation of deoxyriboses and bending of the DNA helix. Calicheamicin is clinically employed as immunoconjugate to antibodies directed against, for example, CD33 in the case of gemtuzumab ozogamicin. Here, we show by the use of the unconjugated drug that calicheamicin-induced apoptosis is independent from death-receptor/FADD-mediated signals. Moreover, calicheamicin triggers apoptosis in a p53-independent manner as shown by the use of p53 knockout cells. Cell death proceeds via activation of mitochondrial permeability transition, cytochrome c release and activation of caspase-9 and -3. The overexpression of Bcl-x L or Bcl-2 strongly inhibited calicheamicin-induced apoptosis. Knockout of Bax abrogated cell death after calicheamicin treatment. Thus, the activation of mitochondria and execution of cell death occur through a fully Baxdependent mechanism. Interestingly, caspase inhibition by the pancaspase-inhibitor zVAD-fmk interfered with mitochondrial activation by calicheamicin. This places caspase activation upstream of the mitochondria and indicates that calicheamicin-triggered apoptosis is enhanced through death receptor-independent activation of the caspase cascade, that is, an amplification loop that is required for full activation of the mitochondrial pathway. Oncogene (2003) 22, 9107-9120.

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Section: Discussionsupporting

confidence: 90%

Induction of apoptosis by enediyne antibiotic calicheamicin ϑII proceeds through a caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner

et al. 2003

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“…Thus, DU145 cells are type II cells that critically depend on the mitochondrial pathway to execute the cell death program upon death receptor ligation. In the same vein, we demonstrated in malignant melanoma that the sensitivity to CD95/Fas-induced apoptosis is impaired upon deregulated overexpression of Bcl-2 (Raisova et al, 2000(Raisova et al, , 2001. Similarly, Bcl-2 overexpression was shown to result in resistance to TRAIL-induced apoptosis in type II cells (Fulda et al, 2002).…”

Section: Discussionmentioning

confidence: 64%

Multidomain Bcl-2 homolog Bax but not Bak mediates synergistic induction of apoptosis by TRAIL and 5-FU through the mitochondrial apoptosis pathway

et al. 2004

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The death ligand TRAIL synergizes with DNA-damaging therapies such as chemotherapeutic drugs or ionizing irradiation. Here, we show that the synergism of TRAIL and 5-fluorouracil (5-FU) and cross-sensitization between TRAIL and 5-FU for induction of apoptosis, entirely depend on Bax proficiency in human DU145 and HCT116 carcinoma cells. DU145 prostate carcinoma cells that have lost Bax protein expression due to mutation fail to release cytochrome c and to activate caspase-3 and -9 when exposed to TRAIL and 5-FU. In contrast, TRAIL sensitized for 5-FU-induced apoptosis and vice versa upon reconstitution of Bax expression. Isobolographic analyses of ED50 doses for 5-FU at increasing TRAIL concentrations showed a clear synergism of TRAIL and 5-FU in Bax-expressing cells. In contrast, the effect was merely additive in DU145 cells lacking Bax. Notably, both DU145 and HCT116 Bax-deficient cells still express Bak. This indicates that Bak is not sufficient to mediate crosssensitization and synergism between 5-FU and TRAIL. Stable overexpression of Bak in DU145 sensitized for epirubicin-induced apoptosis but failed to confer synergy between TRAIL and 5-FU. Moreover, we show by the use of EGFP-tagged Bax and Bak that TRAIL and 5-FU synergistically trigger oligomerization and clustering of Bax but not Bak. These data clearly establish distinct roles for Bax and Bak in linking the TRAIL death receptor pathway to the mitochondrial apoptosis signaling cascade and delineate a higher degree of specificity in signaling for cell death by multidomain Bcl-2 homologs.

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“…53 This was correlated with resistance to CD95/ Fas-induced and ceramide-mediated apoptosis. These data suggest that alterations of mitochondrial processes in tumor cells might also lead to drug resistance.…”

Section: Drug Resistance Via Modulation Of the Apoptotic Pathwaymentioning

confidence: 95%

Drug-resistance in human melanoma

Helmbach¹,

Rossmann²,

Kern³

et al. 2001

Int. J. Cancer

164

137

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Advanced malignant melanoma has a poor prognosis since chemotherapy is mostly ineffective due in part to the intrinsic and/or extrinsic resistance of melanoma cells to systemic treatment with anti-neoplastic agents. The reasons for the chemoresistant phenotype are unknown. The relevance of well-analyzed drug-resistance mechanisms, e.g., intracellular/ extracellular transport and induction of certain enzyme systems, is reviewed. Most anti-cancer drugs kill susceptible cells through induction of apoptosis. Therefore, it appears that differences in the apoptotic pathways which lead to apoptotic deficiency may account for the ability of some tumor cells to resist drug therapy. Human melanomas, which are characteristically drug-resistant, are more likely to have altered apoptotic pathways and fewer pro-apoptotic molecules. Tumor cells with these characteristics are seldom sensitive to drugs. The complexity of the molecular variants involved in signal transduction along apoptotic pathways suggests that the cell may have a variety of possibilities for regulating apoptosis and generating apoptotic deficiency. Thus, apoptosis and apoptotic deficiency should be analyzed to better clarify the mechanisms of melanoma resistance.

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Resistance to CD95/Fas‐induced and ceramide‐mediated apoptosis of human melanoma cells is caused by a defective mitochondrial cytochrome c release

Cited by 89 publications

References 39 publications

Induction of apoptosis by enediyne antibiotic calicheamicin ϑII proceeds through a caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner

Induction of apoptosis by enediyne antibiotic calicheamicin ϑII proceeds through a caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner

Multidomain Bcl-2 homolog Bax but not Bak mediates synergistic induction of apoptosis by TRAIL and 5-FU through the mitochondrial apoptosis pathway

Drug-resistance in human melanoma

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