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Tumor Biology |
Immunology and Oncology Unit, Department of Surgical Sciences, David Maddison Clinical Sciences Building, Newcastle, NSW 2300, Australia
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, TRAIL/apo-2 (4
, 5)
, and apo-3 ligand (6)
. Receptors for the latter, also known as TNF receptor-related apoptosis-mediated protein, DR3, and LARD (7
, 8)
, appear to be mainly related to induction of apoptosis in lymphocytes. In contrast, TRAIL appears to be able to induce apoptosis in a wide range of transformed cell lines but not normal cells (4
, 5)
. TRAIL can induce apoptosis by interaction with two receptors, referred to as DR4 (TRAIL-R1; Refs. 9
and 10
) and DR5/TRAIL-R2/TRICK 2 (11, 12, 13)
. These receptors were found to be widely expressed on normal tissues, which are believed to be protected from apoptosis by two additional receptors, TRAIL-R3/TRID/DcR1/LIT (14, 15, 16, 17)
and TRAIL-R4/DcR2/TRUNDD (18
, 19)
. TRAIL-R3 and -R4 inhibit apoptosis either by acting as decoy receptors or by providing inhibitory signals, perhaps via activation of NF-
B (3
, 20)
. A fifth receptor, OPG, exists in a secreted form and appears to inhibit TRAIL-induced apoptosis by competitive inhibition of TRAIL binding to the death receptors TRAIL-R1 and -R2 (21)
.
In addition to the control of TRAIL-induced apoptosis by expression of "death-inducing" and "decoy" receptors on cells, apoptosis induced by TRAIL and other TNF members may be regulated by inhibitory proteins that bind to Fas-associated death domain or other proteins in the caspase pathway. Cellular FLIP appeared to be more active against TRAIL than against Fas-induced apoptosis of Jurkat cells and was detected in both melanoma cell lines and cutaneous melanoma metastases (22)
. In addition to FLIP, two other IAPs (IAP1 and IAP2) that are induced by activation of NF-B may have similar roles in blocking apoptosis by inhibition of caspase 8 (23)
.
We have shown previously that melanoma cells express receptors for CD40 ligand (24)
, TNF-, and FasL (25)
, but ligands for these receptors were not able to induce apoptosis in the melanoma cells. In contrast, TRAIL was able to induce varying degrees of apoptosis in approximately two-thirds of the melanoma lines tested (26)
. Here, we have examined a large panel of melanoma cells for expression of TRAIL-R at the mRNA and protein level to determine whether the variable induction of apoptosis in melanoma by TRAIL can be related to the expression of the different types of TRAIL-R. We have also examined whether the expression of FLIP protein may be an important determinant of sensitivity to TRAIL-induced apoptosis. The results confirm the importance of TRAIL-R1 or -R2 expression for induction of apoptosis by TRAIL, but the expression of the decoy receptors or FLIP protein did not appear to be related to TRAIL-induced apoptosis of melanoma cells.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MAbs and Recombinant Proteins.
Recombinant human TRAIL (lot no. 6321-19), prepared as described elsewhere (4)
, was supplied by Immunex (Seattle, WA). The preparation was supplied as a leucine zipper fusion protein, which required no further cross-linking for maximal activity. The MAbs against TRAIL-R1 (IgG2a hu TR1-M271; lot no. 7136-07), TRAIL-R2 (IgG1 hu TRAIL-R2-M413; lot no. 5274-96), TRAIL-R3 (IgG1 hu TR3-M430; lot no. 7313-17), and TRAIL-R4 (IgG1 hu TR4-M444; lot no. 7136-15) were also supplied by Immunex. Their specificities and functions are described elsewhere (28)
. The rabbit Ab against FLIP, AL129 (lot no. P3), was prepared as described elsewhere (22)
and was kindly supplied by Dr. J. Tschopp (Ludwig Institute, Lausanne, Switzerland). Isotype control MAbs used were the ID4.5 (IgG2a) MAb against Salmonella typhi, supplied by Dr. L. Ashman (IMVS, Adelaide, South Australia, Australia), and the 107.3 IgG1 MAb (PharMingen, San Diego, CA). The isotype control used for studies on FLIP was purified rabbit IgG, supplied by Sigma Chemical Co. (St. Louis, MO).
RT-PCR Detection of TRAIL, TRAIL-R, OPG, and FLIP.
Total RNA was isolated from 1 x 106 melanoma cells using RNAzol B RNA extraction (Biotecx, Friendswood, TX). The first-strand cDNA was synthesized with a first strand cDNA synthesis kit using Moloney murine leukemia virus reverse transcriptase with oligo(dT) primers (Novagen, Milwaukee, WI). Of the resultant cDNA, 1 µl was used in the 10-µl PCR mix, containing 0.5 µM each relevant primer, 200 µM dNTPs, 2.5 mM MgCl2, 1x reaction buffer IV (Advanced Biotechnologies, Silver Spring, MD), and 0.5 units of thermostable DNA polymerase (Advanced Biotechnologies). The housekeeping gene ß-actin was used as a control. The primer sequences for TRAIL-R are as described elsewhere (29)
. The primer sequences for OPG were designed using the Australian National Genomic Information Service (30)
. Primers for FLIP short and long forms of FLIP were designed using the Primer 3 program database.5
The sequences for the relevant primers were as follows: ß-actin, 5'- ATGGATGATGATATCGCCGCG-3' and 5-CTAGAAGCATTTGCGGTGGACGATGGAGGGGCC-3'; TRAIL-R1, 5'-CTGAGCAACGCAGACTCGCTGTCCAC-3' and 5'-TCCAAGGACACGGCAGAGCCTGTGCCAT-3'; TRAIL-R2, 5'-GCCTCATGGACAATGAGATAAAGGTGGCT-3' and 5'-CCAAATCTCAAAGTACGCACAAACGG-3'; TRAIL-R3, 5'-GAAGAATTTGGTGCCAATGCCACTG-3' and 5'-CTCTTGGACTTGGCTGGGAGATGTG-3'; TRAIL-R4, 5'-CTTTTCCGGCGGCGTTCATGTCCTTC-3' and 5'-GT-TTCTTCCAGGCTGCTTCCCTTTGTAG-3'; OPG, 5'-GTGACGAGTGTCTATACTGCA-3' and 5'-ATCCTCTCTACACTCTCTGCG-3'; and FLIPL, 5'-AATTCAAGGCTCAGAAGCGA-3' and 5'-GGCAGAAACTCTGCTGTTCC3'. The annealing temperatures were 60°C, 61°C, 61°C, 64°C, 60°C, 58°C, and 60°C, respectively.
Samples were amplified for 35 cycles using the FTS-IS thermal sequencer (Corbett Research, Mortlake, Australia). The program consisted of: 1 cycle at 96°C, 58–65°C, and 72°C for 1 min; 35 cycles of 96°C for 30 s, 58–65°C for 35 s, and 72°C for 1 min; and finally 10 min at 72°C. PCR-amplified products were run on a 1.5% agarose gel containing 0.5 µg/ml ethidium bromide and were visualized under UV light.
DNA Sequencing.
The OPG PCR product was cloned in P-GEM T (Promega, Madison, WI) and subjected to thermocycle sequencing reactions, based on the dideoxy termination method (31)
. Likewise, the FLIPL PCR product was sequenced with the same primers used for amplification. The sequencing reactions were determined by using a Perkin-Elmer Catalyst 800 and an automated 377 DNA sequencer (Applied Biosystems, Foster City, CA) at the Sydney University and Prince Alfred Macromolecular Analysis Center (Sydney, New South Wales, Australia).
Southern Blotting.
Three micrograms of genomic DNA from four different melanoma cell lines were digested with HindIII, and the resulting DNA fragments were separated by agarose gel electrophoresis, stained with ethidium bromide, and transferred to a Hybond N+ nylon membrane (Amersham, Castle Hill, NSW Australia) with a VacuGene Pump device from Pharmacia Biotech (Castle Hill, NSW Australia). While the DNA was being transferred to the membrane, the agarose gel was treated as follows: 0.25 M HCl for 15 min and 0.4 M NaOH for 2 h at 50 mbar. The membrane-bound DNA was treated with 2x SSC for 5 min at room temperature.
The TRAIL-R1 and TRAIL-R2 oligonucleotide primers described in the previous section were used to amplify both probes using a digoxigenin labeling and kit (Boehringer Mannheim, Castle Hill, NSW Australia). Membrane hybridization and detection were performed under high-stringency conditions using a digoxigenin DNA detection system. The protocol and buffers used were those described by the manufacturer with the following modification: the chemiluminescence from the labeled membrane was captured by a Kodak (Rochester, NY) digital science Image Station 440CF using a single exposure of 30 min.
Flow Cytometry.
Analysis was carried out using a Becton and Dickinson (Mountain View, CA) FACScan flow cytometer. Appropriate concentrations of MAbs were added to the cells in 100 µl of PBS containing 20% human A serum and incubated for 7 min at room temperature. Cells were either washed twice with PBS and analyzed, if they were directly labeled, or if they were indirectly labeled, cells were then incubated with F(ab')2 fragment affinity isolated FITC-conjugated sheep antimouse immunoglobulin (Silenus; Amrad Biotech, Boronia, Victoria, Australia) plus 20 µl of 100% human serum to block Fc receptors for 7 min at room temperature. A minimum of 5000 cells was analyzed. Studies on permeabilized cells were similar to the methods of Jung et al. (32)
. The cells were fixed in 4% paraformaldehyde and permeabilized in 0.1% saponin in permeabilization buffer, and the Ab to FLIP was added for 30 min at 4°C. The cells were washed and then stained with FITC-labeled F(ab)2 fraction of affinity-isolated sheep antirabbit immunoglobulin (Silenus) at 1:100 dilution for 30 min at 4°C. After washing the cells were analyzed by flow cytometry. The TRAIL-R-negative Me10538 cell line was included as a negative control in all studies on permeabilized cells.
Apoptosis.
Apoptotic cells were determined by the propidium iodide method (33)
. In brief, melanoma cells were adhered overnight in a 24-well plate (Falcon 3047; Becton Dickinson, Lane Cove, Australia) at a concentration of 1 x 105 cells/well in 10% FCS. Cells in suspension were added on the day of the assay. Medium was removed, and 500 µl of fresh medium plus 10% FCS containing the appropriate MAb were added for 30 min at 37° before the addition of TRAIL, FasL, CD40 ligand, or TNF-. Cells were incubated for a further 24 h at 37°C, the medium was removed, and adherent and suspended cells were washed once with PBS. The medium and PBS were placed in 12 x 75 mm Falcon polystyrene tube and centrifuged at 200 x g. One ml of a hypotonic buffer (50 µg/ml propidium iodide in 0.1% sodium citrate plus 0.1% Triton X-100; Sigma) was added directly to the cell pellet of cells grown in suspension or to adhered cells in the 24-well plate and gently pipetted off, then added to the appropriate cell pellet in the Falcon tube. The tubes were placed at 4°C in the dark overnight before flow cytometric analyses. The propidium iodide fluorescence of individual nuclei was measured in the red fluorescence using a FACScan flow cytometer (Becton Dickinson), and the data were registered in a logarithmic scale. At least 104 cells of each sample were analyzed. Apoptotic nuclei appeared as a broad hypodiploid DNA peak, which was easily distinguished from the narrow hyperdiploid peak of nuclei in the melanoma cells.
Western Blot Analysis.
The melanoma cells were harvested by Trypsinization and lysed in cell lysis buffer (34)
containing phenylmethylsulfonyl fluoride, leupeptin, and other protease inhibitors for 1 h on ice. Approximately 3 million cell equivalents were loaded per track, and the protein concentration in each track was checked by visualization with Ponceau-S dye. FLIPL was detected using AL129 polyclonal Ab which was a gift from Dr. J. Tschopp raised against the 197 NH2-terminal amino acids of human FLIP (fused to a flag-tag; Ref. 22
). A Mr of 55,500 was determined for FLIPL using ANGIS nip (30)
. Supernatants after centrifugation were subjected to 12.5% SDS-PAGE. Blotting and detection were performed as described by Radford et al. (35)
, with the following modifications: primary Ab was diluted to 1:200, and detection was performed using Renaissance Western Blot Chemiluminescence Reagent (NEN Life Science Products, Boston, MA) and exposed on to Hyper MP autoradiography film (Amersham).
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RESULTS |
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. TRAIL-R1–R4 products had the expected sizes, as reported elsewhere (29)
. The OPG product had a size of 486 bp. The product was sequenced and shown to correspond to OPG between 345 and 793 bp. FLIPL had a product size of 226 bp, and sequencing of the products confirmed that they were identical to FLIPL between 1552 and 1742 bp in the database.
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. All results were confirmed in at least two assays. The melanoma cell lines have been arranged to illustrate the variable expression of TRAIL-R. Two of the lines, Me10538 and Mel JS, were devoid of mRNA for all TRAIL-R, whereas three expressed mRNA only for one of the receptors. Two lines, Mel RMu and Mel MC, expressed only TRAIL-R1 and -R2 and OPG receptors, and three lines expressed TRAIL-R3 with or without TRAIL-R1 and -R2. The majority (17 of 28) of the lines, however, expressed mRNA for all of the receptors, including that for OPG.
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We examined whether mRNA for FLIP may correlate inversely with TRAIL-induced apoptosis, but this was not apparent by PCR assays. Practically all of the lines expressed mRNA for FLIP, except those with no or only one TRAIL-R (Me10538, Mel JS, Mel SP, and KM3).
Southern Analysis of Genes for TRAIL-R1 and -R2 Receptors.
We examined whether the failure to detect TRAIL-R1 and R2 receptors may result from failure to transcribe the genes concerned or represent loss of genes from the melanoma cell lines. As shown in Fig. 2
, Southern analysis of DNA from the melanoma cell lines MM200, Mel RM, Me10538, and Mel JS with probes for TRAIL-R1 and R2 revealed genes for TRAIL-R1 in the MM200 line but not in Mel RM, Mel JS, or Me10538. TRAIL-R2 was detected in MM200 and Mel RM but not in Me10538 or Mel JS. These results are consistent with those obtained by RT-PCR assays for mRNA shown in Table 1
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. A summary of representative studies on at least two occasions on 20 melanoma lines is shown in Table 2
. TRAIL-R2 protein was expressed on all 20 lines that expressed mRNA for TRAIL-R2, and TRAIL-R1 protein was detected on 12 of 15 lines with mRNA for TRAIL-R1. In contrast, only 5 of 17 lines with mRNA for TRAIL-R3 and 3 of 12 with mRNA for TRAIL-R4 had detectable protein expression. Regression analyses were carried out to examine the correlation of the protein expression of TRAIL-R and FLIP with apoptosis induced by TRAIL. As shown in Fig. 4
, there was a correlation between TRAIL-R1 (r = 0.53) and R2 expression (r = 0.77) and apoptosis but not with TRAIL-R3 or R4 expression. This lack of correlation is further shown by studies on individual lines, e.g., cells from the Me4405 cell line were sensitive to TRAIL-induced apoptosis but had the highest level of expression of TRAIL-R3 and -R4 and FLIP. Melanocytes appeared to express only TRAIL-R2 receptors, despite having mRNA for all four receptors.
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, these lines had the TRAIL-R1 proteins in the cells at comparable levels to cell lines that express TRAIL-R1 on their surface (e.g., Mel FH). Permeabilized melanoma cells that had surface expression of R1 had similar or higher levels than nonpermeabilized cells, e.g., Me4405, Me1007, and Mel JG. Studies on TRAIL-R3 and -R4 expression within permeabilized melanoma cells showed an even more marked disparity compared to membrane expression. As shown in Table 2
, six lines that were negative for surface expression of TRAIL-R3 or -R4 had high levels of the receptors within the cells (e.g., Mel FH and MM200). Cell lines with no mRNA for the receptors, e.g., Me10538, acted as negative controls and no intracellular staining was detected in these cells.
Expression of FLIP in Melanoma.
The Ab against FLIP detected a protein of Mr 55,000, as expected (22)
in Western blots of the Me4405, Mel FH, and MM200 cell lines but not in extracts from IgR3 and Mel CV and the Jurkat T-cell line (Fig. 5)
. These results were similar to the detection of FLIP by flow cytometry on permeabilized melanoma cells shown in Table 2
, e.g., Me4405, Mel FH, and MM200 had FLIP detectable in permeabilized cells and in Western blots, but FLIP was not detectable in Jurkat, Mel CV, and IgR3 by either method. Fig. 4
indicates that the level of FLIP expression did not show an inverse correlation with TRAIL-induced apoptosis. Permeabilized melanocytes also did not have detectable levels of FLIP (Table 2)
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. There was marked variation in sensitivity to TRAIL among the clones, with percentage apoptosis ranging from 13.6 (clone F2) to 100% (clone C3). There was no difference in TRAIL-R and FLIP expression by PCR, but TRAIL-R1 and R2 protein expression showed significant variation between the clones. These variations did not correlate with sensitivity to apoptosis, and the clone with the lowest sensitivity to TRAIL (F2) had the highest TRAIL-R expression. These results were repeated on two occasions with the same results, i.e., the clones appeared to express stable levels of receptor expression and sensitivity to TRAIL-induced apoptosis.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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These studies on a larger panel of melanoma lines extend these findings in several areas.
(a) They show that there is considerable variability in TRAIL-R expression on melanoma lines, which results from at least two factors. One is the loss of genes coding for the receptors. This was apparent for both TRAIL-R1 and -R2 in 4 of the 28 (14%) melanoma lines by RT-PCR and confirmed in two of the lines by Southern analysis. Two of the lines appeared to have lost genes for all of the TRAIL-Rs, and in three lines, all but one of the receptors had been lost. All four TRAIL-Rs were reported to be clustered on 8p22-21 (12) , and it is, therefore, possible that this segment or part thereof was lost from the cell lines and selected in the patients by the survival pressure exerted by TRAIL in their environment.
The second factor underlying variability of TRAIL-R expression appeared to occur at the protein level. Whereas all of the melanoma lines with mRNA for TRAIL-R2 had TRAIL-R2 on their surface, 3 of 15 lines with mRNA for TRAIL-R1 did not express the receptor on the cell surface. This phenomenon was even more marked for TRAIL-R3 and -R4, in that only 5 of 17 and 3 of 12 cell lines, respectively, that had mRNA for the receptors actually expressed the receptor on their surface. It was of much interest to find that many of the cell lines that were negative for receptors on their surface nevertheless appeared to have significant levels within their cytoplasm. Confocal microscopy indicates the TRAIL-R2 receptors are clustered in organelles, similar to the Golgi apparatus, whereas TRAIL-R3 and -R4 are located in the nucleus (data not shown). Previous studies have shown that Fas, the receptor for FasL, is located predominantly within the cell in certain cell types and is rapidly relocated to the cell surface on activation of p53 (36) . To our knowledge, this is the first to suggest that TRAIL-R expression may be regulated in a similar manner at a posttranslational level. Further study on this aspect as well as on additional regulatory mechanisms that may operate at a transcriptional level to regulate TRAIL-R expression is needed.
(b) These studies show that the level of TRAIL-R1 and, particularly, TRAIL-R2 protein expression on the melanoma lines correlated well with their sensitivity to TRAIL-induced apoptosis. However, although this applied to the cell lines overall, certain cell lines were resistant to TRAIL, despite moderate levels of TRAIL-R1 or -R2 expression. This was also evident in clones of melanoma cells established from a cell line. These exhibited different levels of TRAIL-R1 and -R2 protein expression that did not correlate with the marked variation in sensitivity of the clones to TRAIL-induced apoptosis. These findings suggest that the level of TRAIL receptor expression alone is not sufficient to account for sensitivity to TRAIL induced apoptosis and that additional factors that regulate intracellular pathways leading to apoptosis are involved. A prime candidate for this role is the protein FLIP, which binds to caspase 8 and prevents activation of the downstream events leading to apoptosis (22) . FLIP was shown to regulate susceptibility of activated T cells to FasL-induced apoptosis and to block TRAIL-induced apoptosis. Subsequent studies on melanoma cell lines indicated that FLIP protein levels in Western blots correlated with susceptibility to TRAIL-induced apoptosis (29) .
In these studies mRNA for the long form (Mr 55,000) of FLIP was detected in all but 5 of the 28 melanoma lines. However, although FLIP protein expression was detected in 7 of 12 (58%) melanoma cell lines that had mRNA for FLIP, the presence and levels of protein expression did not correlate with resistance to TRAIL-induced apoptosis. Studies on tissue sections showed that 43% of primary melanoma and 63% of metastases expressed FLIP, which is comparable to results on the cell lines (unpublished data). These results may, therefore, indicate that other regulatory proteins that inhibit apoptosis, such as the NF-B induced IAP proteins (23)
, may be involved. The latter were reported to be key proteins responsible for inhibition of apoptosis following interaction with TNF- or other agents that activate NF-B.
(c) To our knowledge the present studies are the first to show that a fifth receptor for TRAIL, OPG, is also expressed at the mRNA level on melanoma lines. Melanocytes did not express mRNA for OPG, but 22 of 28 melanoma lines did. OPG was shown to bind with relatively low affinity to TRAIL and to inhibit TRAIL-induced apoptosis of Jurkat cells (21) . We could not demonstrate a correlation between OPG mRNA expression and susceptibility of melanoma cells to TRAIL-induced apoptosis. Further information about protein expression is needed to examine this aspect further. OPG is a secreted product and may conceivably neutralize TRAIL in the circulation of patients. The natural ligand for OPG is osteoclast differentiation factor (TRANCE/RANKL; Ref. 37 ), so that it might inhibit osteoclast formation around metastases. Further study of these aspects is needed.
These results appear to have important implications for subsequent clinical use of TRAIL. (a) The relatively high proportion of TRAIL-R negative melanoma lines suggest it will be important to assess the TRAIL-R status of tumors in the patient before therapy. (b) The detection of TRAIL-R melanoma with mRNA for TRAIL-R and TRAIL-R protein within the cell but not on the cell surface indicates more information is needed about regulation of TRAIL-R expression. Similarly, the presence of melanoma lines with surface expression of TRAIL that are resistant to TRAIL-induced apoptosis requires more understanding of the regulatory pathways and inhibitors controlling apoptosis induced by TRAIL.
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FOOTNOTES |
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1 Supported by the Melanoma and Skin Cancer Institute, Sydney, the NSW State Cancer Council, and the National Health and Medical Research Council, Australia. 
2 The first two authors contributed equally to this work.
3 To whom requests for reprints should be addressed.
4 The abbreviations used are: TNF, tumor necrosis factor; FasL, Fas ligand; TRAIL, TNF-related apoptosis-inducing ligand; TRAIL-R, TRAIL receptor; NF-B, nuclear factor B; OPG, osteoprotegerin; FLIP, FLICE-inhibitory protein; IAP, inhibitor of apoptosis; MAb, monoclonal antibody; Ab, antibody; RT-PCR, reverse transcription-PCR.
5 Available at http://www.genome.wi.mit.edu//cgi-bin/primer/primer3.cgi.
Received 11/23/98. Accepted 4/ 2/99.
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D. Lane, M. Cote, R. Grondin, M.-C. Couture, and A. Piche Acquired resistance to TRAIL-induced apoptosis in human ovarian cancer cells is conferred by increased turnover of mature caspase-3. Mol. Cancer Ther., March 1, 2006; 5(3): 509 - 521. [Abstract] [Full Text] [PDF]
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X. D. Zhang, J. J. Wu, S. Gillespie, J. Borrow, and P. Hersey Human Melanoma Cells Selected for Resistance to Apoptosis by Prolonged Exposure to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Are More Vulnerable to Necrotic Cell Death Induced by Cisplatin Clin. Cancer Res., February 15, 2006; 12(4): 1355 - 1364. [Abstract] [Full Text] [PDF]
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L. Galligan, D. B. Longley, M. McEwan, T. R. Wilson, K. McLaughlin, and P. G. Johnston Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP Mol. Cancer Ther., December 1, 2005; 4(12): 2026 - 2036. [Abstract] [Full Text] [PDF]
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 P. Horak, D. Pils, G. Haller, I. Pribill, M. Roessler, S. Tomek, R. Horvat, R. Zeillinger, C. Zielinski, and M. Krainer Contribution of Epigenetic Silencing of Tumor Necrosis Factor-Related Apoptosis Inducing Ligand Receptor 1 (DR4) to TRAIL Resistance and Ovarian Cancer Mol. Cancer Res., June 1, 2005; 3(6): 335 - 343. [Abstract] [Full Text] [PDF]
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 I. H. Engels, G. Totzke, U. Fischer, K. Schulze-Osthoff, and R. U. Janicke Caspase-10 Sensitizes Breast Carcinoma Cells to TRAIL-Induced but Not Tumor Necrosis Factor-Induced Apoptosis in a Caspase- 3-Dependent Manner Mol. Cell. Biol., April 1, 2005; 25(7): 2808 - 2818. [Abstract] [Full Text] [PDF]
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 T. Matsuda, A. Almasan, M. Tomita, J.-n. Uchihara, M. Masuda, K. Ohshiro, N. Takasu, H. Yagita, T. Ohta, and N. Mori Resistance to Apo2 Ligand (Apo2L)/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Mediated Apoptosis and Constitutive Expression of Apo2L/TRAIL in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines J. Virol., February 1, 2005; 79(3): 1367 - 1378. [Abstract] [Full Text] [PDF]
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X. Zhang, T.-G. Jin, H. Yang, W. C. DeWolf, R. Khosravi-Far, and A. F. Olumi Persistent c-FLIP(L) Expression Is Necessary and Sufficient to Maintain Resistance to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Mediated Apoptosis in Prostate Cancer Cancer Res., October 1, 2004; 64(19): 7086 - 7091. [Abstract] [Full Text] [PDF]
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 D. C. Spierings, E. G. de Vries, E. Vellenga, F. A. van den Heuvel, J. J. Koornstra, J. Wesseling, H. Hollema, and S. de Jong Tissue Distribution of the Death Ligand TRAIL and Its Receptors J. Histochem. Cytochem., June 1, 2004; 52(6): 821 - 831. [Abstract] [Full Text] [PDF]
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A. Nesterov, M. Nikrad, T. Johnson, and A. S. Kraft Oncogenic Ras Sensitizes Normal Human Cells to Tumor Necrosis Factor-{alpha}-Related Apoptosis-Inducing Ligand-Induced Apoptosis Cancer Res., June 1, 2004; 64(11): 3922 - 3927. [Abstract] [Full Text] [PDF]
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 L. B. Pritzker, M. Scatena, and C. M. Giachelli The Role of Osteoprotegerin and Tumor Necrosis Factor-related Apoptosis-inducing Ligand in Human Microvascular Endothelial Cell Survival Mol. Biol. Cell, June 1, 2004; 15(6): 2834 - 2841. [Abstract] [Full Text] [PDF]
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X. D. Zhang, S. K. Gillespie, J. M. Borrow, and P. Hersey The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells Mol. Cancer Ther., April 1, 2004; 3(4): 425 - 435. [Abstract] [Full Text] [PDF]
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 X. Y. Zhang, X. D. Zhang, J. M. Borrow, T. Nguyen, and P. Hersey Translational Control of Tumor Necrosis Factor-related Apoptosis-inducing Ligand Death Receptor Expression in Melanoma Cells J. Biol. Chem., March 12, 2004; 279(11): 10606 - 10614. [Abstract] [Full Text] [PDF]
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X. D. Zhang, S. K. Gillespie, and P. Hersey Staurosporine induces apoptosis of melanoma by both caspase-dependent and -independent apoptotic pathways Mol. Cancer Ther., February 1, 2004; 3(2): 187 - 197. [Abstract] [Full Text] [PDF]
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N. Harper, M. A. Hughes, S. N. Farrow, G. M. Cohen, and M. MacFarlane Protein Kinase C Modulates Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis by Targeting the Apical Events of Death Receptor Signaling J. Biol. Chem., November 7, 2003; 278(45): 44338 - 44347. [Abstract] [Full Text] [PDF]
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M. Chawla-Sarkar, J. A. Bauer, J. A. Lupica, B. H. Morrison, Z. Tang, R. K. Oates, A. Almasan, J. A. DiDonato, E. C. Borden, and D. J. Lindner Suppression of NF-{kappa}B Survival Signaling by Nitrosylcobalamin Sensitizes Neoplasms to the Anti-tumor Effects of Apo2L/TRAIL J. Biol. Chem., October 10, 2003; 278(41): 39461 - 39469. [Abstract] [Full Text] [PDF]
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 A. Younes and M. E. Kadin Emerging Applications of the Tumor Necrosis Factor Family of Ligands and Receptors in Cancer Therapy J. Clin. Oncol., September 15, 2003; 21(18): 3526 - 3534. [Abstract] [Full Text] [PDF]
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J. H. Song, D. K. Song, M. Herlyn, K. C. Petruk, and C. Hao Cisplatin Down-Regulation of Cellular Fas-associated Death Domain-like Interleukin-1{beta}-converting Enzyme-like Inhibitory Proteins to Restore Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Melanoma Cells Clin. Cancer Res., September 15, 2003; 9(11): 4255 - 4266. [Abstract] [Full Text] [PDF]
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A. Kotelkin, E. A. Prikhod'ko, J. I. Cohen, P. L. Collins, and A. Bukreyev Respiratory Syncytial Virus Infection Sensitizes Cells to Apoptosis Mediated by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand J. Virol., September 1, 2003; 77(17): 9156 - 9172. [Abstract] [Full Text] [PDF]
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 R. Greil, G. Anether, K. Johrer, and I. Tinhofer Tracking death dealing by Fas and TRAIL in lymphatic neoplastic disorders: pathways, targets, and therapeutic tools J. Leukoc. Biol., September 1, 2003; 74(3): 311 - 330. [Abstract] [Full Text] [PDF]
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D. J. Buchsbaum, T. Zhou, W. E. Grizzle, P. G. Oliver, C. J. Hammond, S. Zhang, M. Carpenter, and A. F. LoBuglio Antitumor Efficacy of TRA-8 Anti-DR5 Monoclonal Antibody Alone or in Combination with Chemotherapy and/or Radiation Therapy in a Human Breast Cancer Model Clin. Cancer Res., September 1, 2003; 9(10): 3731 - 3741. [Abstract] [Full Text] [PDF]
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D. C. J. Spierings, E. G. E. de Vries, W. Timens, H. J. M. Groen, H. M. Boezen, and S. de Jong Expression of TRAIL and TRAIL Death Receptors in Stage III Non-Small Cell Lung Cancer Tumors Clin. Cancer Res., August 1, 2003; 9(9): 3397 - 3405. [Abstract] [Full Text] [PDF]
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N. K. Sah, A. Munshi, J. F. Kurland, T. J. McDonnell, B. Su, and R. E. Meyn Translation Inhibitors Sensitize Prostate Cancer Cells to Apoptosis Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) by Activating c-Jun N-terminal Kinase J. Biol. Chem., May 30, 2003; 278(23): 20593 - 20602. [Abstract] [Full Text] [PDF]
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X. Yang, M. S. Merchant, M. E. Romero, M. Tsokos, L. H. Wexler, U. Kontny, C. L. Mackall, and C. J. Thiele Induction of Caspase 8 by Interferon {gamma} Renders Some Neuroblastoma (NB) Cells Sensitive to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) but Reveals That a Lack of Membrane TR1/TR2 Also Contributes to TRAIL Resistance in NB Cancer Res., March 1, 2003; 63(5): 1122 - 1129. [Abstract] [Full Text] [PDF]
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T. M. LaVallee, X. H. Zhan, M. S. Johnson, C. J. Herbstritt, G. Swartz, M. S. Williams, W. A. Hembrough, S. J. Green, and V. S. Pribluda 2-Methoxyestradiol Up-Regulates Death Receptor 5 and Induces Apoptosis through Activation of the Extrinsic Pathway Cancer Res., January 15, 2003; 63(2): 468 - 475. [Abstract] [Full Text] [PDF]
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J. Strater, U. Hinz, H. Walczak, G. Mechtersheimer, K. Koretz, C. Herfarth, P. Moller, and T. Lehnert Expression of TRAIL and TRAIL Receptors in Colon Carcinoma: TRAIL-R1 Is an Independent Prognostic Parameter Clin. Cancer Res., December 1, 2002; 8(12): 3734 - 3740. [Abstract] [Full Text] [PDF]
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K. Kandasamy and R. K. Srivastava Role of the Phosphatidylinositol 3'-Kinase/PTEN/Akt Kinase Pathway in Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Non-Small Cell Lung Cancer Cells Cancer Res., September 1, 2002; 62(17): 4929 - 4937. [Abstract] [Full Text] [PDF]
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V. Poulaki, C. S. Mitsiades, V. Kotoula, S. Tseleni-Balafouta, A. Ashkenazi, D. A. Koutras, and N. Mitsiades Regulation of Apo2L/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Thyroid Carcinoma Cells Am. J. Pathol., August 1, 2002; 161(2): 643 - 654. [Abstract] [Full Text] [PDF]
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M. Chawla-Sarkar, D. W. Leaman, B. S. Jacobs, and E. C. Borden IFN-{beta} Pretreatment Sensitizes Human Melanoma Cells to TRAIL/Apo2 Ligand-Induced Apoptosis J. Immunol., July 15, 2002; 169(2): 847 - 855. [Abstract] [Full Text] [PDF]
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C. Xiao, B. F. Yang, N. Asadi, F. Beguinot, and C. Hao Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Death-inducing Signaling Complex and Its Modulation by c-FLIP and PED/PEA-15 in Glioma Cells J. Biol. Chem., July 5, 2002; 277(28): 25020 - 25025. [Abstract] [Full Text] [PDF]
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F. Guo, R. Nimmanapalli, S. Paranawithana, S. Wittman, D. Griffin, P. Bali, E. O'Bryan, C. Fumero, H. G. Wang, and K. Bhalla Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis Blood, May 1, 2002; 99(9): 3419 - 3426. [Abstract] [Full Text] [PDF]
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N. Mitsiades, C. S. Mitsiades, V. Poulaki, K. C. Anderson, and S. P. Treon Intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human multiple myeloma cells Blood, March 15, 2002; 99(6): 2162 - 2171. [Abstract] [Full Text] [PDF]
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 S. Frese, T. Brunner, M. Gugger, A. Uduehi, and R. A. Schmid Enhancement of Apo2L/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis in non-small cell lung cancer cell lines by chemotherapeutic agents without correlation to the expression level of cellular protease caspase-8 inhibitory protein J. Thorac. Cardiovasc. Surg., January 1, 2002; 123(1): 168 - 174. [Abstract] [Full Text] [PDF]
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A. Krueger, S. Baumann, P. H. Krammer, and S. Kirchhoff FLICE-Inhibitory Proteins: Regulators of Death Receptor-Mediated Apoptosis Mol. Cell. Biol., December 15, 2001; 21(24): 8247 - 8254. [Full Text] [PDF]
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J. J. Lum, A. A. Pilon, J. Sanchez-Dardon, B. N. Phenix, J. E. Kim, J. Mihowich, K. Jamison, N. Hawley-Foss, D. H. Lynch, and A. D. Badley Induction of Cell Death in Human Immunodeficiency Virus-Infected Macrophages and Resting Memory CD4 T Cells by TRAIL/Apo2L J. Virol., November 15, 2001; 75(22): 11128 - 11136. [Abstract] [Full Text] [PDF]
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D. Chatterjee, I. Schmitz, A. Krueger, K. Yeung, S. Kirchhoff, P. H. Krammer, M. E. Peter, J. H. Wyche, and P. Pantazis Induction of Apoptosis in 9-Nitrocamptothecin-treated DU145 Human Prostate Carcinoma Cells Correlates with de Novo Synthesis of CD95 and CD95 Ligand and Down-Regulation of c-FLIPshort Cancer Res., October 1, 2001; 61(19): 7148 - 7154. [Abstract] [Full Text] [PDF]
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X. D. Zhang, X. Y. Zhang, C. P. Gray, T. Nguyen, and P. Hersey Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis of Human Melanoma Is Regulated by Smac/DIABLO Release from Mitochondria Cancer Res., October 1, 2001; 61(19): 7339 - 7348. [Abstract] [Full Text] [PDF]
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C. S. Mitsiades, S. P. Treon, N. Mitsiades, Y. Shima, P. Richardson, R. Schlossman, T. Hideshima, and K. C. Anderson TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications Blood, August 1, 2001; 98(3): 795 - 804. [Abstract] [Full Text] [PDF]
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M. Cuello, S. A. Ettenberg, A. S. Clark, M. M. Keane, R. H. Posner, M. M. Nau, P. A. Dennis, and S. Lipkowitz Down-Regulation of the erbB-2 Receptor by Trastuzumab (Herceptin) Enhances Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated Apoptosis in Breast and Ovarian Cancer Cell Lines that Overexpress erbB-2 Cancer Res., June 1, 2001; 61(12): 4892 - 4900. [Abstract] [Full Text] [PDF]
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A. V. Franco, X. D. Zhang, E. Van Berkel, J. E. Sanders, X. Y. Zhang, W. D. Thomas, T. Nguyen, and P. Hersey The Role of NF-{{kappa}}B in TNF-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis of Melanoma Cells J. Immunol., May 1, 2001; 166(9): 5337 - 5345. [Abstract] [Full Text] [PDF]
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S. Liu, Y. Yu, M. Zhang, W. Wang, and X. Cao The Involvement of TNF-{{alpha}}-Related Apoptosis-Inducing Ligand in the Enhanced Cytotoxicity of IFN-{{beta}}-Stimulated Human Dendritic Cells to Tumor Cells J. Immunol., May 1, 2001; 166(9): 5407 - 5415. [Abstract] [Full Text] [PDF]
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R. Di Pietro, P. Secchiero, R. Rana, D. Gibellini, G. Visani, K. Bemis, L. Zamai, S. Miscia, and G. Zauli Ionizing radiation sensitizes erythroleukemic cells but not normal erythroblasts to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity by selective up-regulation of TRAIL-R1 Blood, May 1, 2001; 97(9): 2596 - 2603. [Abstract] [Full Text] [PDF]
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N. Mitsiades, V. Poulaki, C. Mitsiades, and M. Tsokos Ewing's Sarcoma Family Tumors Are Sensitive to Tumor Necrosis Factor-related Apoptosis-inducing Ligand and Express Death Receptor 4 and Death Receptor 5 Cancer Res., March 1, 2001; 61(6): 2704 - 2712. [Abstract] [Full Text]
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C. Hao, F. Beguinot, G. Condorelli, A. Trencia, E. G. Van Meir, V. W. Yong, I. F. Parney, W. H. Roa, and K. C. Petruk Induction and Intracellular Regulation of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Mediated Apotosis in Human Malignant Glioma Cells Cancer Res., February 1, 2001; 61(3): 1162 - 1170. [Abstract] [Full Text]
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A. Eggert, M. A. Grotzer, T. J. Zuzak, B. R. Wiewrodt, R. Ho, N. Ikegaki, and G. M. Brodeur Resistance to Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Neuroblastoma Cells Correlates with a Loss of Caspase-8 Expression Cancer Res., February 1, 2001; 61(4): 1314 - 1319. [Abstract] [Full Text]
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S. Lacour, A. Hammann, A. Wotawa, L. Corcos, E. Solary, and M.-T. Dimanche-Boitrel Anticancer Agents Sensitize Tumor Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated Caspase-8 Activation and Apoptosis Cancer Res., February 1, 2001; 61(4): 1645 - 1651. [Abstract] [Full Text]
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R. Nimmanapalli, M. Porosnicu, D. Nguyen, E. Worthington, E. O’Bryan, C. Perkins, and K. Bhalla Cotreatment with STI-571 Enhances Tumor Necrosis Factor {{alpha}}-related Apoptosis-inducing Ligand (TRAIL or Apo-2L)- induced Apoptosis of Bcr-Abl-positive Human Acute Leukemia Cells Clin. Cancer Res., February 1, 2001; 7(2): 350 - 357. [Abstract] [Full Text]
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R. Nimmanapalli, C. L. Perkins, M. Orlando, E. O’Bryan, D. Nguyen, and K. N. Bhalla Pretreatment with Paclitaxel Enhances Apo-2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis of Prostate Cancer Cells by Inducing Death Receptors 4 and 5 Protein Levels Cancer Res., January 1, 2001; 61(2): 759 - 763. [Abstract] [Full Text]
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J. Wen, N. Ramadevi, D. Nguyen, C. Perkins, E. Worthington, and K. Bhalla Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute leukemia cells Blood, December 1, 2000; 96(12): 3900 - 3906. [Abstract] [Full Text] [PDF]
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W. D. Thomas, X. D. Zhang, A. V. Franco, T. Nguyen, and P. Hersey TNF-Related Apoptosis-Inducing Ligand-Induced Apoptosis of Melanoma Is Associated with Changes in Mitochondrial Membrane Potential and Perinuclear Clustering of Mitochondria J. Immunol., November 15, 2000; 165(10): 5612 - 5620. [Abstract] [Full Text] [PDF]
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N. Özören, K. Kim, T. F. Burns, D. T. Dicker, A. D. Moscioni, and W. S. El-Deiry The Caspase 9 Inhibitor Z-LEHD-FMK Protects Human Liver Cells while Permitting Death of Cancer Cells Exposed to Tumor Necrosis Factor-related Apoptosis-inducing Ligand Cancer Res., November 1, 2000; 60(22): 6259 - 6265. [Abstract] [Full Text]
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J. M. Routes, S. Ryan, A. Clase, T. Miura, A. Kuhl, T. A. Potter, and J. L. Cook Adenovirus E1A Oncogene Expression in Tumor Cells Enhances Killing by TNF-Related Apoptosis-Inducing Ligand (TRAIL) J. Immunol., October 15, 2000; 165(8): 4522 - 4527. [Abstract] [Full Text] [PDF]
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M. Leverkus, H. Walczak, A. McLellan, H.-W. Fries, G. Terbeck, E.-B. Brocker, and E. Kampgen Maturation of dendritic cells leads to up-regulation of cellular FLICE-inhibitory protein and concomitant down-regulation of death ligand-mediated apoptosis Blood, October 1, 2000; 96(7): 2628 - 2631. [Abstract] [Full Text] [PDF]
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C. S. Seitz, H. Deng, K. Hinata, Q. Lin, and P. A. Khavari Nuclear Factor {{kappa}}B Subunits Induce Epithelial Cell Growth Arrest Cancer Res., August 1, 2000; 60(15): 4085 - 4092. [Abstract] [Full Text]
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N. Mitsiades, V. Poulaki, S. Tseleni-Balafouta, D. A. Koutras, and I. Stamenkovic Thyroid Carcinoma Cells Are Resistant to FAS-mediated Apoptosis But Sensitive to Tumor Necrosis Factor-related Apoptosis-inducing Ligand Cancer Res., August 1, 2000; 60(15): 4122 - 4129. [Abstract] [Full Text]
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S. Hopkins-Donaldson, J.-L. Bodmer, K. B. Bourloud, C. B. Brognara, J. Tschopp, and N. Gross Loss of Caspase-8 Expression in Highly Malignant Human Neuroblastoma Cells Correlates with Resistance to Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis Cancer Res., August 1, 2000; 60(16): 4315 - 4319. [Abstract] [Full Text]
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S. Fulda, E. Meyer, and K.-M. Debatin Metabolic Inhibitors Sensitize for CD95 (APO-1/Fas)-induced Apoptosis by Down-Regulating Fas-associated Death Domain-like Interleukin 1-Converting Enzyme Inhibitory Protein Expression Cancer Res., July 1, 2000; 60(14): 3947 - 3956. [Abstract] [Full Text]
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L. Zamai, P. Secchiero, S. Pierpaoli, A. Bassini, S. Papa, E. S. Alnemri, L. Guidotti, M. Vitale, and G. Zauli TNF-related apoptosis-inducing ligand (TRAIL) as a negative regulator of normal human erythropoiesis Blood, June 15, 2000; 95(12): 3716 - 3724. [Abstract] [Full Text] [PDF]
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X. D. Zhang, A. V. Franco, T. Nguyen, C. P. Gray, and P. Hersey Differential Localization and Regulation of Death and Decoy Receptors for TNF-Related Apoptosis-Inducing Ligand (TRAIL) in Human Melanoma Cells J. Immunol., April 15, 2000; 164(8): 3961 - 3970. [Abstract] [Full Text] [PDF]
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K. Kim, M. J. Fisher, S.-Q. Xu, and W. S. El-Deiry Molecular Determinants of Response to TRAIL in Killing of Normal and Cancer Cells Clin. Cancer Res., February 1, 2000; 6(2): 335 - 346. [Abstract] [Full Text]
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S. H. Lee, M. S. Shin, H. S. Kim, H. K. Lee, W. S. Park, S. Y. Kim, J. H. Lee, S. Y. Han, J. Y. Park, R. R. Oh, et al. Alterations of the DR5/TRAIL Receptor 2 Gene in Non-Small Cell Lung Cancers Cancer Res., November 1, 1999; 59(22): 5683 - 5686. [Abstract] [Full Text] [PDF]
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D. J. Panka, T. Mano, T. Suhara, K. Walsh, and J. W. Mier Phosphatidylinositol 3-Kinase/Akt Activity Regulates c-FLIP Expression in Tumor Cells J. Biol. Chem., March 2, 2001; 276(10): 6893 - 6896. [Abstract] [Full Text] [PDF]
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D. Bernard, B. Quatannens, B. Vandenbunder, and C. Abbadie Rel/NF-kappa B Transcription Factors Protect against Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis by Up-regulating the TRAIL Decoy Receptor DcR1 J. Biol. Chem., July 13, 2001; 276(29): 27322 - 27328. [Abstract] [Full Text] [PDF]
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E. R. McDonald III, P. C. Chui, P. F. Martelli, D. T. Dicker, and W. S. El-Deiry Death Domain Mutagenesis of KILLER/DR5 Reveals Residues Critical for Apoptotic Signaling J. Biol. Chem., April 27, 2001; 276(18): 14939 - 14945. [Abstract] [Full Text] [PDF]
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T. F. Burns and W. S. El-Deiry Identification of Inhibitors of TRAIL-induced Death (ITIDs) in the TRAIL-sensitive Colon Carcinoma Cell Line SW480 Using a Genetic Approach J. Biol. Chem., October 5, 2001; 276(41): 37879 - 37886. [Abstract] [Full Text] [PDF]
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 A. K. Simon, O. Williams, J. Mongkolsapaya, B. Jin, X. N. Xu, H. Walczak, and G. R. Screaton Tumor necrosis factor-related apoptosis-inducing ligand in T cell development: Sensitivity of human thymocytes PNAS, April 24, 2001; 98(9): 5158 - 5163. [Abstract] [Full Text] [PDF]
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