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Department of Immunobiology, Immunex Corp., Seattle, WA 98101
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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 (TNF-related apoptosis-inducing ligand) is a recently identified member of the TNF family that, like FasL, is a type II membrane protein capable of inducing apoptotic cell death in a variety of cell types (11, 12). TRAIL can interact with four distinct receptors: DR4 (13), DR5/TRAIL-R2/TRICK2 (14, 15, 16, 17), TRID/DcR1/TRAIL-R3/LIT (14, 15, 18, 19), and TRAIL-R4/DcR2 (20, 21) (hereafter referred to as TRAIL-R1, -R2, -R3, and -R4, respectively). Both TRAIL-R1 and TRAIL-R2 are type I transmembrane proteins that contain cytoplasmic death domains and, upon ligation, mediate apoptosis (13, 14, 15, 16). In contrast, neither TRAIL-R3 (which is glycosylphosphatidylinositol (GPI) linked) nor TRAIL R-4 (which is a type I transmembrane protein that contains an incomplete cytoplasmic death domain) mediates apoptosis upon ligation with TRAIL (14, 15, 18, 20, 21). Because they lack the ability to directly signal cell death, TRAIL-R3 and TRAIL-R4 have been hypothesized as being protective receptors, either by acting as "decoy" receptors (14, 15, 21) or via transduction of an antiapoptotic signal (20).
The mRNA distribution of TRAIL, TRAIL-R1, and TRAIL-R2 is broad, with many of the same tissues expressing transcripts for both TRAIL and these TRAIL receptors, whereas the distribution of TRAIL-R3 and -R4 is more restricted (11, 13, 16, 18, 20). Although the in vivo role of the TRAIL/TRAIL receptor system is not currently known, in vitro studies have found normal tissues to be resistant to TRAIL-induced death, and some tumor cell lines to be sensitive to the cytotoxic effects of TRAIL (11, 12). While it has been suggested that the presence or the absence of the nonsignaling receptors may determine whether a cell is resistant or sensitive, respectively, to TRAIL-induced apoptosis, it seems unlikely that this would be the only mechanism controlling survival upon TRAIL binding. Regardless of the mechanism of selectivity, these early reports still implicate TRAIL as a potential tumor therapeutic, where tumor cells would be induced to undergo apoptosis and cells in normal tissues would not. In the current study we compared the effectiveness of TRAIL to that of a panel of TNF family cytokines for their ability to induce death in a number of human melanoma cell lines. Our results provide information concerning the activation and regulation of TRAIL-induced apoptosis, and suggest a potential use for TRAIL as a treatment for human melanoma.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The tetrapeptide caspase inhibitors, carbobenzyloxy-Val-Ala-Asp (OMe) fluoromethyl ketone (z-VAD-fmk), carbobenzyloxy-Asp-Glu-Val-Asp fluoromethyl ketone (z-DEVD-fmk), and carbobenzyloxy-Ile-Glu(OMe)-Thr-Asp(OMe)-fluoromethyl ketone (z-IETD-fmk), were obtained from Enzyme Systems Products (Livermore, CA). Stock solutions of the inhibitors were prepared in DMSO and stored at 4°C. The Abs against caspase-8 (provided by Dr. M. Peter, Heidelberg, Germany), caspase-3 (Transduction Laboratories, Lexington, KY), and poly(ADP-ribose) polymerase (PARP; PharMingen, San Diego, CA) were used according to the manufacturer’s instruction. Antiserum against human FLICE-inhibitory protein (FLIP) was generated by injecting rats with a peptide spanning amino acids 2 to 26 (SAEVIHQVEEALDTDEKEMLFLCRD) (22). The FLIP peptide was synthesized on solid support resins (Novabiochem, La Jolla, CA) on an Applied Biosystems 433A peptide synthesizer (Foster City, CA) using F-moc chemistry (23). Peptides were cleaved from the resin using a cleavage mixture (1/2/2/3/40, ethanedithiol/thioanisole/water/phenol/trifluoroacetic acid) and were purified on a Vydac C18 column (Resolution Systems, Wilmette, IL) using a 0 to 60% acetonitrile gradient in 0.1% trifluoroacetic acid. The identity and purity of the peptide were confirmed by HPLC, amino acid analysis, and mass spectrometry using a PerSeptive Biosystems Voyager-DE STR Biospectrometer (Framingham, MA).
Cell lines
Human melanoma cell lines were provided by Dr. M. Herlyn (WM 9, 35, 98-1, 164, 793, 1205-Ln, 1791-C, and 3211; Wistar Institute, Philadelphia, PA) and were cultured in DMEM supplemented with 10% FBS, penicillin, streptomycin, and glutamine. Normal human epidermal melanocytes were obtained from Clonetics (San Diego, CA) and cultured as directed.
In vitro killing of human cell lines with TNF family molecules
Tumor sensitivity to TRAIL, CD40L, TNF-
, and FasL was assayed
by incubating the cells in 96-well plates (5 x 104
cells/well) with purified LZ-TRAIL (300 ng/ml) (16), LZ-CD40L (20
µg/ml), TNF- (300 ng/ml), or culture supernatant containing
LZ-FasL (1 µg/ml, as determined by Western blot) for 24 h. The
indicated values were starting concentrations, followed by threefold
dilutions. In some experiments, actinomycin D (10 ng/ml) or
cycloheximide (10 µM) was added to the culture medium immediately
before the addition of LZ-TRAIL. Cell death was determined by crystal
violet staining as previously described (24). Results are presented as
the percent cell death: 1 - (OD of cells treated with LZ-TRAIL
per OD of cells not treated with LZ-TRAIL) x 100. Cell lines were
considered sensitive if there was >30% cell death induced by the
highest concentration of LZ-TRAIL, LZ-CD40L, TNF-, or LZ-FasL.
Flow cytometry
Surface expressions of TRAIL receptor(s), CD40, and Fas were determined by flow cytometric analysis by measuring the binding of LZ-TRAIL, LZ-CD40L, and anti-Fas Ab (M3). Briefly, cells were incubated with 10 µg/ml LZ-TRAIL, LZ-CD40L, or M3 in 3% BSA in PBS (PBSA) for 30 min on ice. Following three washes with PBS, cells were incubated with a mouse anti-leucine zipper Ab (M15; 10 µg/ml in 3% PBSA) for 30 min on ice. Finally, after three washes in PBS, the cells were incubated for 30 min on ice with a goat anti-mouse FITC-conjugated Ab (diluted 1/200 in 3% PBSA; Sigma, St. Louis, MO). Cells were analyzed on a FACScan (Becton Dickinson, San Jose, CA).
Western blot analysis
Cells from each melanoma line were lysed in PBS containing 1% Nonidet P-40, 0.35 mg/ml PMSF, 9.5 µg/ml leupeptin, and 13.7 µg/ml pepstatin A. The lysed cells were centrifuged at 14,000 x g to remove cellular debris. Protein concentrations of the extracts were determined by the colorimetric bicinchoninic acid analysis (Pierce, Rockford, IL). Equal amounts of protein were separated by SDS-PAGE, transferred to nitrocellulose membrane (Novex, San Diego, CA), and blocked with 5% nonfat dry milk in PBS-Tween-20 (0.05%, v/v) overnight. The membrane was incubated with the anti-caspase-8, anti-caspase-3, or anti-PARP Abs (diluted according to the manufacturer’s instructions) or with FLIP antiserum (diluted 1/1000) for 1 h. After washing, the membrane was incubated with an anti-mouse horseradish peroxidase or anti-rat horseradish peroxidase Ab (diluted 1/1000; Amersham, Arlington Heights, IL) for 1 h. Following several washes, the blots were developed by chemiluminescence according to the manufacturer’s protocol (Renaissance chemiluminescence reagent, DuPont-New England Nuclear, Boston, MA).
RT-PCR for human TRAIL receptors
Total RNA was isolated from various human cell lines with TRIzol reagent (Life Technologies, Gaithersburg, MD) according to the manufacturer’s instructions. RNA samples (1 µg each) were tested for DNA contamination by 30 cycles of PCR with human ß-actin primers. After it was shown that there was no DNA contamination, cDNA synthesis was performed using an RNA PCR kit (Perkin-Elmer, Norwalk, CT) with the supplied oligo(dT)16 primer. RT was performed using a thermal program of 25°C for 10 min, 42°C for 30 min, and 95°C for 5 min. PCR reactions were performed using the following primers: ß-actin (forward: 5'-GAAACTACCTTCAACTCCATC-3'; reverse: 5'-CGAGGCCAGGATGGAGCCGCC-3'), TRAIL-R1 (forward: 5'-CTGAGCAACGCAGACTCGCTGTCCAC-3'; reverse: 5'-TCCAAGGACACGGCAGAGCCTGTGCCAT-3'), TRAIL-R2 (forward: 5'-GCCTCATGGACAATGAGATAAAGGTGGCT-3'; reverse: 5'-CCAAATCTCAAAGTACGCACAAACGG-3'), TRAIL-R3 (forward: 5'-GAAGAATTTGGTGCCAATGCCACTG-3'; reverse: 5'-CTCTTGGACTTGGCTGGGAGATGTG-3'), and TRAIL-R4 (forward: 5'-CTTTTCCGGCGGCGTTCATGTCCTTC-3'; reverse: 5'-GTTTCTTCCAGGCTGCTTCCCTTTGTAG-3'), giving products of 219, 506, 502, 612, and 453 bp, respectively. Human ß-actin PCR cycle conditions were 95°C for 45 s, 55°C for 1 min, and 72°C for 45 s for 30 cycles. Human TR-1, -2, and -3 conditions were 94°C for 1 min, 55°C for 1 min, and 72°C for 1 min for 30 cycles. Human TR-4 cycle conditions were 95°C for 4 min 15 s, followed by 30 cycles of 95°C for 45 s, 60°C for 45 s, and 72°C for 45 s. Samples were resolved on a 2% agarose gel and visualized with ethidium bromide.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Based on the fact that members of the TNF family are cytotoxic to
a number of human tumor cell lines (25), we were interested in
comparing the effectiveness of TRAIL to induce death in human melanoma
cell lines and normal melanocytes to that of three other TNF family
molecules (CD40L, FasL, and TNF). Five of the lines (WM 9, WM 35, WM
98-1, WM 793, and WM 1205 Ln) were sensitive to the cytotoxic effects
of TRAIL, whereas three lines (WM 164, WM 1791-C, and WM 3211) and
normal human melanocytes were resistant (Fig. 1
). In contrast, all the cell lines were
resistant to CD40L, FasL, and TNF.
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). CD40L binding was
also detected with most of the cell lines, but much lower binding was
seen with WM 98-1 and WM 164 cells, which may explain why these cell
lines were resistant to CD40L-induced apoptosis. Thus, resistance of
melanoma cells to cytokine-induced apoptosis is not due to the lack of
cognate receptors, but instead appears to be due to other regulatory
mechanisms.
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Apoptotic cell death induced by TNF or FasL is a rapid biochemical
process characterized by the activation of a cascade of intracellular
proteases, or caspases, and cleavage of numerous intracellular proteins
(26, 27). It has been recently suggested that many of the molecules
involved in other death receptor-mediated apoptosis also participate in
TRAIL-induced death (28, 29). Thus, we wanted to determine the kinetics
of caspase activation and cellular protein cleavage during
TRAIL-induced apoptosis. The TRAIL-sensitive melanoma WM 1205 Ln was
exposed to TRAIL for various periods of time, after which the cells
were lysed, and the cellular proteins were separated by SDS-PAGE for
Western blot analysis of caspase-8 (FLICE) and caspase-3 (CPP32)
activation and PARP cleavage. Caspase-8 activation was detected within
5 min after TRAIL addition to WM 1205 Ln (Fig. 3A). Similarly, activation of
caspase-3 was detected within 15 min, and PARP cleavage was detected
within 30 min after the addition of TRAIL. These results demonstrate
the rapid activation of a caspase cascade similar to that seen with
other death receptors, leading to the cleavage of intracellular
proteins within TRAIL-sensitive cells. Since one of the early
biochemical events in apoptotic cell death is the cleavage of PARP from
its native 116-kDa form to an 85-kDa fragment (30), we were interested
to determine whether PARP cleavage occurred in all the TRAIL-sensitive
melanoma cell lines while it remained uncleaved in the TRAIL-resistant
melanomas. Indeed, PARP cleavage was only seen in the TRAIL-sensitive
lines and not in the resistant lines (Fig. 3B).
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). In
contrast, DEVD was only able to partially inhibit the cytotoxic effects
of TRAIL. Equal concentrations of the peptide vehicle (DMSO) did not
inhibit TRAIL-induced death. The decreased ability of DEVD to inhibit
death compared with that of IETD and VAD may result from differences in
the ability of the peptides to enter the cell. These results
demonstrate that TRAIL-induced apoptosis shares many of the same
characteristics as apoptosis induced by other TNF family molecules.
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The demonstration that both sensitive and resistant cell lines
bind LZ-TRAIL indicated the expression of at least one of the TRAIL
receptors on the surface of these tumor cells. Unfortunately, no
receptor-specific Abs are available at this time to individually
examine the surface expression of these proteins. Thus, oligonucleotide
primers derived from unique regions in each receptor sequence were used
in RT-PCR to determine which TRAIL receptor transcripts were present in
the melanoma cells. Figure 5A
shows these primer pairs are specific, in that PCR products only
resulted when the proper cDNA template was present, and the results
from melanoma lines are shown in Figure 5B. All the
melanomas were positive for TRAIL-R2 mRNA, whereas four of eight were
positive for TRAIL-R1, five of eight were positive for TRAIL-R3, and
only one was positive for TRAIL-R4. Although there were melanomas (WM
164 and WM 1791) in which TRAIL-R3 and/or -R4 expression correlated
with resistance to TRAIL-inducing killing, several of the
TRAIL-sensitive lines (WM 9, WM 793, and WM 1205 Ln) were also positive
for TRAIL-R3 and/or -R4 mRNA. Alternatively, WM 3211, which is
resistant to the cytotoxic effects of TRAIL, tested negative for
TRAIL-R3 and -R4 mRNA. Thus, our results indicate that there is no
strict correlation between the expression of mRNA encoding TRAIL-R3 or
-R4 and sensitivity or resistance to TRAIL-mediated apoptosis.
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It is known that the inhibition of protein synthesis can increase
the level of sensitivity of target cells that are otherwise resistant
to FasL- or TNF-induced death (31). To test the possibility that
TRAIL-induced death might also be enhanced by protein synthesis
inhibitors, TRAIL-resistant melanoma lines were pretreated with either
actinomycin D or cycloheximide, followed by LZ-TRAIL. The melanoma cell
line WM 164 is resistant to the cytotoxic effects of TRAIL, but is
readily killed upon the addition of either agent to the assay (Fig. 6A). Similar results were
observed with WM 1791 and WM 3211. Examination of these cells after
actinomycin D treatment by RT-PCR found no alteration in the pattern of
TRAIL receptor mRNA expression (data not shown). Furthermore,
conversion of this cell from resistant to sensitive by actinomycin D
correlated with caspase-8 activation and PARP cleavage as detected by
Western blot analysis (Fig. 6B). These results not only
indicate that the "death machinery" is intact and functional within
the TRAIL-resistant melanoma lines, but indicate that its function is
being inhibited by an intracellular inhibitor(s) of the cell death
signaling pathway.
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The fact that protein synthesis inhibitors can render resistant
melanoma cells sensitive to TRAIL suggests that these cells are
synthesizing an intracellular inhibitor(s) of apoptosis. Although Bcl-2
and Bcl-xL have been shown to protect cells from apoptosis
induced by FasL and TNF (32, 33, 34, 35), only FLIP has been shown to inhibit
TRAIL-induced death (22). Thus, FLIP levels in the eight melanoma cell
lines used in this study were examined by Western blot with an
anti-FLIP antiserum. The TRAIL-resistant melanomas (WM 164, WM
1791, and WM 3211) all expressed high levels of FLIP, whereas FLIP
levels in the TRAIL-sensitive melanomas (WM 9, WM 35, WM 98-1, WM 793,
and WM 1205 Ln) were low or undetectable (Fig. 7A). Caspase-8 levels were
also examined in the eight cell lines and were roughly equivalent. The
detection of low levels of FLIP in the TRAIL-sensitive lines (WM 9, WM
35, and WM 98-1) suggests that the intracellular concentration of FLIP
with respect to that of caspase-8 may determine whether a cell is
susceptible to TRAIL.
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B. If FLIP has a high turnover rate
within the cell, then the intracellular levels should rapidly decrease
over time when the cells are exposed to actinomycin D. The
FLIP+, TRAIL-resistant melanoma WM 3211 was incubated with
actinomycin D for various lengths of time, after which the cells were
lysed, and caspase-8 and FLIP protein levels were determined by Western
blotting. Whereas caspase-8 levels did not dramatically change with
actinomycin D treatment, FLIP levels were found to decrease within 1 to
2 h of adding actinomycin D and were significantly lower after
24 h. These results provide additional support for the premise
that protection from TRAIL-induced death in melanoma cells is regulated
by the ratio of FLIP protein within the cell to the components of the
TRAIL receptor death pathway, presumably caspase-8.
Seeing that changes in FLIP levels could be detected within 1 to
2 h of actinomycin D addition, we were interested to see how these
changes correlated with the gain in susceptibility to TRAIL-induced
death. WM 3211 cells were incubated with actinomycin D for 2, 4, or
6 h, followed by a wash and addition of fresh culture medium.
TRAIL was then added, and cell death was determined as previously
described. In correlation with the results shown in Figure 7B, the sensitivity of WM 3211 to TRAIL increased with the
length of actinomycin D pretreatment (Fig. 8). TRAIL-induced death was significantly
increased after actinomycin D pretreatment for just 2 h, while
pretreating for 6 h increased death levels close to those seen in
the control group (actinomycin D and TRAIL for 24 h). Thus, the
results indicate that TRAIL-induced death in melanoma cell lines is
primarily regulated by the intracellular concentration of FLIP, and not
simply by the expression of decoy receptors.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The identification of four distinct receptors for TRAIL, two with death-inducing ability and two without, was initially proposed as a mechanism by which sensitivity to TRAIL-induced apoptosis was regulated, since the mRNA distribution of TRAIL-R3 and TRAIL-R4 was primarily in normal tissues and was absent in the tumor cells tested (14, 15, 21). However, examination of TRAIL receptor mRNA in the human melanoma cell lines found no correlation between the expression of the putative protective TRAIL receptors (TRAIL-R3 and -R4) and resistance or sensitivity to TRAIL. Analysis of a larger panel of human tumors (>60 different lines) has also found no correlation between the expression of the protective TRAIL receptors and resistance to TRAIL (our manuscript in preparation). In contrast, the data presented here clearly demonstrate the importance of intracellular regulators of apoptosis induced by TRAIL. Levels of the apoptosis inhibitor FLIP were highest in the TRAIL-resistant lines and were low or absent in the sensitive lines. Additionally, experiments examining the effect of actinomycin D on FLIP in the TRAIL-resistant melanoma WM 3211 revealed a clear correlation between the increase in sensitivity to TRAIL with decreased FLIP levels. These observations indicate that the expression of the decoy TRAIL receptors does not confer resistance in unmanipulated tumor cells, but, rather, that there are multiple factors that may function to provide protection against the cytotoxic effects of TRAIL.
To date, there has been limited study of the signaling events associated with TRAIL receptor ligation. At the time that TRAIL-R1 and TRAIL-R2 were first described it appeared that the TRAIL receptor system used novel adapter proteins, since neither FADD nor TRADD bound to TRAIL-R1 or TRAIL-R2 (13, 14). However, subsequent studies reported contradictory findings by showing direct binding of FADD and TRADD to these two TRAIL receptors and inhibition of TRAIL-induced death with dominant negative forms of FADD and TRADD (16, 28, 29, 40). The discrepancies between these studies may be explained by differences in the relative levels of expression of these molecules in the transfectants used in the experiments. When coupled with data showing that caspase inhibitory peptides block TRAIL-induced apoptosis, it seems evident that many of the death proteases involved in TNF- and FasL-induced apoptosis are also activated by TRAIL receptor ligation. To our knowledge, the data presented here are the first report on the involvement of these molecules in TRAIL-mediated apoptosis in melanomas.
The use of the caspase inhibitors and Abs in this study permitted a
finer analysis of the TRAIL receptor signaling cascade. Data presented
in Figure 3A clearly show that caspase-8 is a proximal
component of this pathway, followed by caspase-3. However, it is also
likely that other caspases are activated, which could explain why the
caspase inhibitor DEVD did not block death as completely as VAD or
IETD. A recent study by Schneider et al. (29) showed the
potential formation of heterotrimeric TRAIL receptor complexes of
TRAIL-R1 and TRAIL-R2, and that ligation of such a mixed receptor may
lead to the activation of multiple death cascades within the cell. It
is also possible that the caspase-8 homologue caspase-10 (FLICE2/Mch4)
(41, 42) may bind to the TRAIL receptor signaling complex, which could
then activate other death pathways.
Studies examining human melanomas have defined five major stages in the progression of the disease. These stages are common acquired nevus, dysplastic nevus, radial growth phase (RGP) primary melanoma, vertical growth phase (VGP) primary melanoma, and metastatic melanoma (43). Whereas melanoma cell lines generated from RGP primary melanomas are rarely established, VGP and metastatic melanoma cell lines can be more easily established. The melanoma cell lines used in the experiments presented here were generated from RGP primary melanomas (WM 35 and WM 3211), VGP primary melanomas (WM 98-1 and WM 793), and metastatic melanomas (WM 9, WM 164, and WM 1205Ln) (44). While no correlation could be found between TRAIL sensitivity and the stages from which the cell lines were made (TRAIL-sensitive and TRAIL-resistant cell lines were derived from both primary and metastatic melanomas), our results do suggest that TRAIL could be used to treat human melanoma at each of the various stages and potentially remove any undetected tumors in the body distant from the primary lesion.
Malignant melanoma remains one of the more difficult types of cancer to successfully treat, and with the incidence of melanoma increasing at a rate of approximately 5%/yr over the last 30 yr in Caucasians it continues to be a leading cause of death throughout the world (45). Here we described the mechanism by which TRAIL induces apoptosis in human melanoma cells and a means by which some melanomas remain resistant to TRAIL. Although the results also demonstrate the potential use of TRAIL as a cytotoxic agent against human melanoma, further studies of the mechanisms of TRAIL-mediated cytotoxicity and resistance are required to further assess the potential use of TRAIL as an anticancer therapeutic in vivo.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: CD40L, CD40 ligand; FasL, Fas ligand; TRAIL, TNF-related apoptosis-inducing ligand; PARP, poly(ADP-ribose) polymerase; FLIP, FLICE-inhibitory protein; PBSA, 3% BSA in PBS; RGP, radial growth phase; VGP, vertical growth phase.
Received for publication March 12, 1998. Accepted for publication May 21, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 7:13.[Medline]
B pathway. Immunity 7:821.[Medline]
B. Immunity 7:831.[Medline]
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L. M. Thai, A. Labrinidis, S. Hay, V. Liapis, S. Bouralexis, K. Welldon, B. J. Coventry, D. M. Findlay, and A. Evdokiou Apo2l/Tumor necrosis factor-related apoptosis-inducing ligand prevents breast cancer-induced bone destruction in a mouse model. Cancer Res., May 15, 2006; 66(10): 5363 - 5370. [Abstract] [Full Text] [PDF]
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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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S. Martin, D. C. Phillips, K. Szekely-Szucs, L. Elghazi, F. Desmots, and J. A. Houghton Cyclooxygenase-2 Inhibition Sensitizes Human Colon Carcinoma Cells to TRAIL-Induced Apoptosis through Clustering of DR5 and Concentrating Death-Inducing Signaling Complex Components into Ceramide-Enriched Caveolae Cancer Res., December 15, 2005; 65(24): 11447 - 11458. [Abstract] [Full Text] [PDF]
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P. Horak, D. Pils, A. Kaider, A. Pinter, K. Elandt, C. Sax, C. C. Zielinski, R. Horvat, R. Zeillinger, A. Reinthaller, et al. Perturbation of the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Cascade in Ovarian Cancer: Overexpression of FLIPL and Deregulation of the Functional Receptors DR4 and DR5 Clin. Cancer Res., December 15, 2005; 11(24): 8585 - 8591. [Abstract] [Full Text] [PDF]
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 B. Sukumaran, J. A. Carlyon, J.-L. Cai, N. Berliner, and E. Fikrig Early Transcriptional Response of Human Neutrophils to Anaplasma phagocytophilum Infection Infect. Immun., December 1, 2005; 73(12): 8089 - 8099. [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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E. M. Jung, J. H. Lim, T. J. Lee, J.-W. Park, K. S. Choi, and T. K. Kwon Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5) Carcinogenesis, November 1, 2005; 26(11): 1905 - 1913. [Abstract] [Full Text] [PDF]
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N. Oka, S. Nakahara, Y. Takenaka, T. Fukumori, V. Hogan, H.-o. Kanayama, T. Yanagawa, and A. Raz Galectin-3 Inhibits Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by Activating Akt in Human Bladder Carcinoma Cells Cancer Res., September 1, 2005; 65(17): 7546 - 7553. [Abstract] [Full Text] [PDF]
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H. S. Kim, I. Chang, J. Y. Kim, K.-H. Choi, and M.-S. Lee Caspase-Mediated p65 Cleavage Promotes TRAIL-Induced Apoptosis Cancer Res., July 15, 2005; 65(14): 6111 - 6119. [Abstract] [Full Text] [PDF]
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S. Shetty, B. A. Graham, J. G. Brown, X. Hu, N. Vegh-Yarema, G. Harding, J. T. Paul, and S. B. Gibson Transcription Factor NF-{kappa}B Differentially Regulates Death Receptor 5 Expression Involving Histone Deacetylase 1 Mol. Cell. Biol., July 1, 2005; 25(13): 5404 - 5416. [Abstract] [Full Text] [PDF]
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 E. Ishikawa, M. Nakazawa, M. Yoshinari, and M. Minami Role of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand in Immune Response to Influenza Virus Infection in Mice J. Virol., June 15, 2005; 79(12): 7658 - 7663. [Abstract] [Full Text] [PDF]
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 H. Li, J. Y. Niederkorn, S. Neelam, and H. Alizadeh Resistance and Susceptibility of Human Uveal Melanoma Cells to TRAIL-Induced Apoptosis Arch Ophthalmol, May 1, 2005; 123(5): 654 - 661. [Abstract] [Full Text] [PDF]
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 J.-P. Herbeuval, A. Boasso, J.-C. Grivel, A. W. Hardy, S. A. Anderson, M. J. Dolan, C. Chougnet, J. D. Lifson, and G. M. Shearer TNF-related apoptosis-inducing ligand (TRAIL) in HIV-1-infected patients and its in vitro production by antigen-presenting cells Blood, March 15, 2005; 105(6): 2458 - 2464. [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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Y.-H. Kim, J.-W. Park, J.-Y. Lee, and T. K. Kwon Sodium butyrate sensitizes TRAIL-mediated apoptosis by induction of transcription from the DR5 gene promoter through Sp1 sites in colon cancer cells Carcinogenesis, October 1, 2004; 25(10): 1813 - 1820. [Abstract] [Full Text] [PDF]
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K. Izeradjene, L. Douglas, A. Delaney, and J. A. Houghton Influence of Casein Kinase II in Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Human Rhabdomyosarcoma Cells Clin. Cancer Res., October 1, 2004; 10(19): 6650 - 6660. [Abstract] [Full Text] [PDF]
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 J. K. Riley, J. M. Heeley, A. H. Wyman, E. L. Schlichting, and K. H. Moley TRAIL and KILLER Are Expressed and Induce Apoptosis in the Murine Preimplantation Embryo Biol Reprod, September 1, 2004; 71(3): 871 - 877. [Abstract] [Full Text] [PDF]
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J.-Z. Qin, L. Stennett, P. Bacon, B. Bodner, M. J.C. Hendrix, R. E.B. Seftor, E. A. Seftor, N. V. Margaryan, P. M. Pollock, A. Curtis, et al. p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas Mol. Cancer Ther., August 1, 2004; 3(8): 895 - 902. [Abstract] [Full Text] [PDF]
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T. J. Kemp, J. M. Moore, and T. S. Griffith Human B Cells Express Functional TRAIL/Apo-2 Ligand after CpG-Containing Oligodeoxynucleotide Stimulation J. Immunol., July 15, 2004; 173(2): 892 - 899. [Abstract] [Full Text] [PDF]
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W. Matsuyama, M. Yamamoto, I. Higashimoto, K.-i. Oonakahara, M. Watanabe, K. Machida, T. Yoshimura, N. Eiraku, M. Kawabata, M. Osame, et al. TNF-related apoptosis-inducing ligand is involved in neutropenia of systemic lupus erythematosus Blood, July 1, 2004; 104(1): 184 - 191. [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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M. Taniai, A. Grambihler, H. Higuchi, N. Werneburg, S. F. Bronk, D. J. Farrugia, S. H. Kaufmann, and G. J. Gores Mcl-1 Mediates Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Resistance in Human Cholangiocarcinoma Cells Cancer Res., May 15, 2004; 64(10): 3517 - 3524. [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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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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D. J. Panka and J. W. Mier Canstatin Inhibits Akt Activation and Induces Fas-dependent Apoptosis in Endothelial Cells J. Biol. Chem., September 26, 2003; 278(39): 37632 - 37636. [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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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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S. Ray and A. Almasan Apoptosis Induction in Prostate Cancer Cells and Xenografts by Combined Treatment with Apo2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand and CPT-11 Cancer Res., August 1, 2003; 63(15): 4713 - 4723. [Abstract] [Full Text] [PDF]
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J. H. Kim, M. Ajaz, A. Lokshin, and Y. J. Lee Role of Antiapoptotic Proteins in Tumor Necrosis Factor-related Apoptosis-inducing Ligand and Cisplatin-augmented Apoptosis Clin. Cancer Res., August 1, 2003; 9(8): 3134 - 3141. [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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T. J. Kemp, B. D. Elzey, and T. S. Griffith Plasmacytoid Dendritic Cell-Derived IFN-{alpha} Induces TNF-Related Apoptosis-Inducing Ligand/Apo-2L-Mediated Antitumor Activity by Human Monocytes Following CpG Oligodeoxynucleotide Stimulation J. Immunol., July 1, 2003; 171(1): 212 - 218. [Abstract] [Full Text] [PDF]
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Q. Liu, S. Hilsenbeck, and Y. Gazitt Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL Blood, May 15, 2003; 101(10): 4078 - 4087. [Abstract] [Full Text] [PDF]
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 Y. YANG and X. YU Regulation of apoptosis: the ubiquitous way FASEB J, May 1, 2003; 17(8): 790 - 799. [Abstract] [Full Text] [PDF]
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 J.-P. Herbeuval, C. Lambert, O. Sabido, M. Cottier, P. Fournel, M. Dy, and C. Genin Macrophages From Cancer Patients: Analysis of TRAIL, TRAIL Receptors, and Colon Tumor Cell Apoptosis J Natl Cancer Inst, April 16, 2003; 95(8): 611 - 621. [Abstract] [Full Text] [PDF]
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X. Chen, K. Kandasamy, and R. K. Srivastava Differential Roles of RelA (p65) and c-Rel Subunits of Nuclear Factor {kappa}B in Tumor Necrosis Factor-related Apoptosis-inducing Ligand Signaling Cancer Res., March 1, 2003; 63(5): 1059 - 1066. [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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B. F. Yang, C. Xiao, W. H. Roa, P. H. Krammer, and C. Hao Calcium/Calmodulin-dependent Protein Kinase II Regulation of c-FLIP Expression and Phosphorylation in Modulation of Fas-mediated Signaling in Malignant Glioma Cells J. Biol. Chem., February 21, 2003; 278(9): 7043 - 7050. [Abstract] [Full Text] [PDF]
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M. Leverkus, M. R. Sprick, T. Wachter, T. Mengling, B. Baumann, E. Serfling, E.-B. Brocker, M. Goebeler, M. Neumann, and H. Walczak Proteasome Inhibition Results in TRAIL Sensitization of Primary Keratinocytes by Removing the Resistance-Mediating Block of Effector Caspase Maturation Mol. Cell. Biol., February 1, 2003; 23(3): 777 - 790. [Abstract] [Full Text]
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 C. W. Xiao, X. Yan, Y. Li, S. A. G. Reddy, and B. K. Tsang Resistance of Human Ovarian Cancer Cells to Tumor Necrosis Factor {alpha} Is a Consequence of Nuclear Factor {kappa}B-Mediated Induction of Fas-Associated Death Domain-Like Interleukin-1{beta}-Converting Enzyme-Like Inhibitory Protein Endocrinology, February 1, 2003; 144(2): 623 - 630. [Abstract] [Full Text] [PDF]
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J. R. Basile, A. Eichten, V. Zacny, and K. Munger NF-{kappa}B-Mediated Induction of p21Cip1/Waf1 by Tumor Necrosis Factor {alpha} Induces Growth Arrest and Cytoprotection in Normal Human Keratinocytes Mol. Cancer Res., February 1, 2003; 1(4): 262 - 270. [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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 S. Barille-Nion, B. Barlogie, R. Bataille, P. L. Bergsagel, J. Epstein, R. G. Fenton, J. Jacobson, W. M. Kuehl, J. Shaughnessy, and G. Tricot Advances in Biology and Therapy of Multiple Myeloma Hematology, January 1, 2003; 2003(1): 248 - 278. [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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 H. Higuchi, S. F. Bronk, M. Taniai, A. Canbay, and G. J. Gores Cholestasis Increases Tumor Necrosis Factor-Related Apoptotis-Inducing Ligand (TRAIL)-R2/DR5 Expression and Sensitizes the Liver to TRAIL-Mediated Cytotoxicity J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 461 - 467. [Abstract] [Full Text] [PDF]
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H.-o. Lee, J. M. Herndon, R. Barreiro, T. S. Griffith, and T. A. Ferguson TRAIL: A Mechanism of Tumor Surveillance in an Immune Privileged Site J. Immunol., November 1, 2002; 169(9): 4739 - 4744. [Abstract] [Full Text] [PDF]
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T. Naka, K. Sugamura, B. L. Hylander, M. B. Widmer, Y. M. Rustum, and E. A. Repasky Effects of Tumor Necrosis Factor-related Apoptosis-inducing Ligand Alone and in Combination with Chemotherapeutic Agents on Patients' Colon Tumors Grown in SCID Mice Cancer Res., October 15, 2002; 62(20): 5800 - 5806. [Abstract] [Full Text] [PDF]
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A. Spencer, S.-L. Yeh, K. Koutrevelis, C. Baulch-Brown ;, N. Mitsiades, C. Mitsiades, K. C. Anderson, and S. P. Treon TRAIL-induced apoptosis of authentic myeloma cells does not correlate with the procaspase-8/cFLIP ratio Blood, September 26, 2002; 100(8): 3049 - 3050. [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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Y. Kim, N. Suh, M. Sporn, and J. C. Reed An Inducible Pathway for Degradation of FLIP Protein Sensitizes Tumor Cells to TRAIL-induced Apoptosis J. Biol. Chem., June 14, 2002; 277(25): 22320 - 22329. [Abstract] [Full Text] [PDF]
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 F. H. Igney and P. H. Krammer Immune escape of tumors: apoptosis resistance and tumor counterattack J. Leukoc. Biol., June 1, 2002; 71(6): 907 - 920. [Abstract] [Full Text] [PDF]
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T. S. Griffith, J. M. Fialkov, D. L. Scott, T. Azuhata, R. D. Williams, N. R. Wall, D. C. Altieri, and A. D. Sandler Induction and Regulation of Tumor Necrosis Factor-related Apoptosis-inducing Ligand/Apo-2 Ligand-mediated Apoptosis in Renal Cell Carcinoma Cancer Res., June 1, 2002; 62(11): 3093 - 3099. [Abstract] [Full Text] [PDF]
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M. M. van Noesel, S. van Bezouw, G. S. Salomons, P. A. Voute, R. Pieters, S. B. Baylin, J. G. Herman, and R. Versteeg Tumor-specific Down-Regulation of the Tumor Necrosis Factor-related Apoptosis-inducing Ligand Decoy Receptors DcR1 and DcR2 Is Associated with Dense Promoter Hypermethylation Cancer Res., April 1, 2002; 62(7): 2157 - 2161. [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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W. Roth, F. Stenner-Liewen, K. Pawlowski, A. Godzik, and J. C. Reed Identification and Characterization of DEDD2, a Death Effector Domain-containing Protein J. Biol. Chem., February 22, 2002; 277(9): 7501 - 7508. [Abstract] [Full Text] [PDF]
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 K. Takeda, M. J. Smyth, E. Cretney, Y. Hayakawa, N. Kayagaki, H. Yagita, and K. Okumura Critical Role for Tumor Necrosis Factor-related Apoptosis-inducing Ligand in Immune Surveillance Against Tumor Development J. Exp. Med., January 14, 2002; 195(2): 161 - 169. [Abstract] [Full Text] [PDF]
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 M. Fotin-Mleczek, F. Henkler, D. Samel, M. Reichwein, A. Hausser, I. Parmryd, P. Scheurich, J. A. Schmid, and H. Wajant Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8 J. Cell Sci., January 7, 2002; 115(13): 2757 - 2770. [Abstract] [Full Text] [PDF]
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A. R. Jazirehi, C.-P. Ng, X.-H. Gan, G. Schiller, and B. Bonavida Adriamycin Sensitizes the Adriamycin-resistant 8226/Dox40 Human Multiple Myeloma Cells to Apo2L/Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated (TRAIL) Apoptosis Clin. Cancer Res., December 1, 2001; 7(12): 3874 - 3883. [Abstract] [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. Y. Zang, R. G. Goodwin, M. R. Loken, E. Bryant, and H. J. Deeg Expression of tumor necrosis factor-related apoptosis-inducing ligand, Apo2L, and its receptors in myelodysplastic syndrome: effects on in vitro hemopoiesis Blood, November 15, 2001; 98(10): 3058 - 3065. [Abstract] [Full Text] [PDF]
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H. Thakkar, X. Chen, F. Tyan, S. Gim, H. Robinson, C. Lee, S. K. Pandey, C. Nwokorie, N. Onwudiwe, and R. K. Srivastava Pro-survival Function of Akt/Protein Kinase B in Prostate Cancer Cells. RELATIONSHIP WITH TRAIL RESISTANCE J. Biol. Chem., October 12, 2001; 276(42): 38361 - 38369. [Abstract] [Full Text] [PDF]
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H. Higuchi, S. F. Bronk, Y. Takikawa, N. Werneburg, R. Takimoto, W. El-Deiry, and G. J. Gores The Bile Acid Glycochenodeoxycholate Induces TRAIL-Receptor 2/DR5 Expression and Apoptosis J. Biol. Chem., October 12, 2001; 276(42): 38610 - 38618. [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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P.-O. Vidalain, O. Azocar, H. Yagita, C. Rabourdin-Combe, and C. Servet-Delprat Cytotoxic Activity of Human Dendritic Cells Is Differentially Regulated by Double-Stranded RNA and CD40 Ligand J. Immunol., October 1, 2001; 167(7): 3765 - 3772. [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. Chawla-Sarkar, D. W. Leaman, and E. C. Borden Preferential Induction of Apoptosis by Interferon (IFN)-{beta} Compared with IFN-{{alpha}}2: Correlation with TRAIL/Apo2L Induction in Melanoma Cell Lines Clin. Cancer Res., June 1, 2001; 7(6): 1821 - 1831. [Abstract] [Full Text] [PDF]
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I. F. Pollack, M. Erff, and A. Ashkenazi Direct Stimulation of Apoptotic Signaling by Soluble Apo2L/Tumor Necrosis Factor-related Apoptosis-inducing Ligand Leads to Selective Killing of Glioma Cells Clin. Cancer Res., May 1, 2001; 7(5): 1362 - 1369. [Abstract] [Full Text]
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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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A. Chuntharapai, K. Dodge, K. Grimmer, K. Schroeder, S. A. Marsters, H. Koeppen, A. Ashkenazi, and K. J. Kim Isotype-Dependent Inhibition of Tumor Growth In Vivo by Monoclonal Antibodies to Death Receptor 4 J. Immunol., April 15, 2001; 166(8): 4891 - 4898. [Abstract] [Full Text] [PDF]
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R. D. Pettersen, G. Bernard, M. K. Olafsen, M. Pourtein, and S. O. Lie CD99 Signals Caspase-Independent T Cell Death J. Immunol., April 15, 2001; 166(8): 4931 - 4942. [Abstract] [Full Text] [PDF]
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S. Kagawa, C. He, J. Gu, P. Koch, S.-J. Rha, J. A. Roth, S. A. Curley, L. C. Stephens, and B. Fang Antitumor Activity and Bystander Effects of the Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Gene Cancer Res., April 1, 2001; 61(8): 3330 - 3338. [Abstract] [Full Text]
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E. H. Alexander, J. L. Bento, F. M. Hughes Jr., I. Marriott, M. C. Hudson, and K. L. Bost Staphylococcus aureus and Salmonella enterica Serovar Dublin Induce Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Expression by Normal Mouse and Human Osteoblasts Infect. Immun., March 1, 2001; 69(3): 1581 - 1586. [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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P. J. Frost, L. H. Butterfield, V. B. Dissette, J. S. Economou, and B. Bonavida Immunosensitization of Melanoma Tumor Cells to Non-MHC Fas-Mediated Killing by MART-1-Specific CTL Cultures J. Immunol., March 1, 2001; 166(5): 3564 - 3573. [Abstract] [Full Text] [PDF]
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D.-W. Seol, J. Li, M.-H. Seol, S.-Y. Park, R. V. Talanian, and T. R. Billiar Signaling Events Triggered by Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL): Caspase-8 Is Required for TRAIL-induced Apoptosis Cancer Res., February 1, 2001; 61(3): 1138 - 1143. [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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H. Matsuzaki, B. M. Schmied, A. Ulrich, J. Standop, M. B. Schneider, S. K. Batra, K. S. Picha, and P. M. Pour Combination of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) and Actinomycin D Induces Apoptosis Even in TRAIL-resistant Human Pancreatic Cancer Cells Clin. Cancer Res., February 1, 2001; 7(2): 407 - 414. [Abstract] [Full Text]
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O. Salvucci, M. Carsana, I. Bersani, G. Tragni, and A. Anichini Antiapoptotic Role of Endogenous Nitric Oxide in Human Melanoma Cells Cancer Res., January 1, 2001; 61(1): 318 - 326. [Abstract] [Full Text]
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