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Department of Pediatric Onco-Hematology, Centre Hospitalier Universitaire Vaudois, CH1011 Lausanne [S. H-D., K. B. B., C. B. B., N. G.], and Institute of Biochemistry, University of Lausanne, CH1066 Epalinges [J-L. B., J. T.], Switzerland
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Introduction |
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TRAIL receptors TRAIL-R1/DR4 and TRAIL-R2/DR5/TRICK are members of the TNF death receptor family that trigger a cascade of events on binding to cell surface TRAIL involving caspase activation and resulting in DNA fragmentation and cell death (3) . In contrast to FasL/CD95L and TNF, which are both toxic after systemic administration, TRAIL has no adverse effects on normal tissues and can selectively kill implanted tumor cells (4) . However, some tumor cells are resistant to TRAIL-induced apoptosis, with the expression of inhibitory molecules such as cFLIP (5) or decoy receptors TRAIL-R3/TRID/DcR1 and TRAIL-R4/DcR2 (6) being proposed as underlying mechanisms of TRAIL resistance. cFLIP overexpression blocks both Fas and TRAIL pathways by preventing the recruitment and activation of the initiator caspase-8 (7) , whereas TRAIL decoy receptors are thought to block TRAIL signaling by competing with TRAIL-R1 and TRAIL-R2. These may not be the only existing mechanisms of resistance to TRAIL because no correlation was found between TRAIL resistance and cFLIP or TRAIL decoy receptor mRNA expression in human melanoma (3 , 8) .
In this study, we investigated the sensitivity of NB cell lines of invasive (N-type) and noninvasive (S-type) phenotypes (9 , 10) to TRAIL and the underlying mechanisms used by invasive NB cells to evade apoptosis.
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Materials and Methods |
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Primary Antibodies.
Mouse antihuman Fas antibodies were from PharMingen (Becton
Dickinson), agonistic mouse antihuman Fas antibodies (clone CH11) were
from Upstate Biotechnology, mouse antihuman caspase-8 antibodies were
from Medical and Biological Laboratories, and rabbit antihuman
caspase-8 antibodies were from Santa Cruz Biotechnology. Mouse
anti-FADD and caspase-3 antibodies were obtained from Transduction
Laboratories, and mouse anti-caspase-10 antibodies were obtained from
Millennium Biotechnology. Anti-TRAIL-R2 (clone AL142) was
generated in rabbits by injecting TRAILR2:Fc (Alexis Biochemicals).
Mouse anti-N-CAM (UJ13A) was kindly provided by Dr. John
Kemshead (Bristol University, Bristol, United Kingdom), and
HLA-ABC (B9-12-1) has been described previously (11)
.
Cell Viability Assays.
Cells (100 µl; 105 cells/well in 96-well
plates) were incubated in the presence of anti-Fas CH11 or soluble
recombinant TRAIL and cross-linking mouse anti-FLAG antibody M2 (Alexis
Biochemicals). After 16 h, tetrazolium dye solution from the Cell
titer kit (Promega) was added, and the production of blue formazan
product produced by viable cells was measured at an absorbance of
570 nm. Assays were performed in quadruplicate, mean cell viability was
compared with untreated controls, and SDs were calculated. The
percentage of cell viability was also evaluated by staining cells with
0.5% crystal violet (Fluka). Absorbance was measured at 570 nm. Each
assay was performed at least three times, and the percentage of cell
viability compared with untreated controls was calculated. The
percentage of cell death was calculated as 100 - the
percentage of cell viability.
RT-PCR Analysis.
DNA-free RNA was prepared using the SV total RNA purification
kit (Promega). RNA (1 µg) was used in RT-PCR reactions using the
Promega Access RT-PCR kit. RNA samples were tested for DNA
contamination by 40 cycles of PCR with each pair of primers used.
Primers used to amplify Fas, TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4,
and caspase-10 have been described elsewhere (12, 13, 14)
.
Primers used to amplify human ß-actin, cFLIP, and caspase-8 cDNA are
as follows: (a) ß-actin, (5') TGACGGGGTCACCCACAC
TGTGCCCATCTA and (3') CTAGAAGCATTTGCGGTGGACGATGGAGGG; (b)
cFLIP, (5') GGAGGCTTATGTCTGCTGAAGTCATC and (3')
GGGGAATTCCTTCTGATTCCTGAATGG; and (c) caspase-8, (5')
TCTGGAGCATCTGCTGTCTG and (3') CCTGCCTGGTGTCTGAAGTT. RT-PCR reactions
were performed using a thermal program of 48°C for 45 min; 94°C for
5 min; 40 cycles of 94°C for 1 min, 55°C for 1 min, and 72°C for
1 min; and then 72°C for 10 min. A total of 30% of the final PCR
products were loaded onto a 1% agarose gel.
Flow Cytometric Analysis.
Cells were washed in FACS buffer (RPMI 1640, 10% FCS, and 2
mM EDTA) and then stained with antihuman Fas MAb or rabbit
antihuman TRAIL-R2 antibodies, followed by goat secondary antibodies
conjugated to FITC (Caltag Laboratories). A total of 10,000 events were
collected on a FACScan II (Becton Dickinson).
Western and Southern Blotting.
Cellular 1% NP40 (30 µg) extracts were boiled in sample buffer and
analyzed by 10% SDS-PAGE under reducing conditions and by Western
blotting. Blots were saturated with 5% skim milk and 0.5% Tween 20 in
PBS and revealed using mouse anti-FADD, anti-caspase-3, anti-caspase-8,
or anti-caspase-10 MAbs followed by incubation with
peroxidase-conjugated secondary antibody (Jackson ImmunoResearch).
Bound antibodies were detected using the enhanced chemiluminescence kit
(Amersham International) according to the manufacturer’s instructions.
Genomic DNA was isolated by lysis in a solution of 10 mM
Tris-HCl (pH 10.5), 1 mM EDTA, 150 mM NaCl, and
0.5% SDS and digested twice for 90 min in 20 mg/ml proteinase K
(Boehringer Mannheim) at 56°C, and then two chloroform/phenol
extractions were performed. Southern blotting was then carried out as
described previously (15)
, and nylon filters were
hybridized with full-length caspase-8 cDNA or the pNB-1 NMYC
probe kindly provided by Dr. M. Schwab (DFKZ, Heidelberg,
Germany).
Caspase-3 Activity Assay.
Caspase-3 activity was assayed by mixing 10 µl of post nuclear lysate
(30–40 µg protein) with 10 volumes of reaction buffer [10
mM Tris-HCl (pH 7.4), 0.1%
3-[(3-cholamidopropyl)dimethylammonio]-1 -propanesulfonic acid, 2
mM MgCl2, 1 mM DTT, 5
mM EGTA, and 150 mM NaCl] containing 50
µM of a fluorogenic caspase-3 substrate
(Ac-DEVD-AMC; Alexis Biochemicals). The mixture was incubated
for 60 min in a black ELISA titer plate, and fluorescence was measured
in a Fluoroskan ELISA reader (excitation, 355 nm; emission, 460 nm).
The caspase-3 activity was expressed as a fold increase compared with
nontreated cells, and background was deduced using the lysis buffer as
a control. All values are normalized with respect to the protein
content in the sample measured by the Bio-Rad protein assay.
Immunohistochemistry.
Frozen sections (7 µm) were fixed in acetone, permeabilized for
caspase-8 staining in 1% Triton X-100 in Tris-buffered saline, blocked
in 2 g/liter BSA, and then incubated overnight with rabbit
anti-caspase-8 antibodies, followed by biotinylated goat anti-rabbit
antibody (DAKO) and avidin-alkaline phosphatase conjugate (ABComplex,
DAKO). Color was developed using Fast Red TR/Napthol AS-MX (Sigma),
followed by counterstaining with hematoxylin. For N-CAM and HLA class 1
staining, frozen sections were fixed and blocked as described above and
incubated for 2 h in primary antibody followed by rabbit
anti-mouse alkaline phosphatase and swine anti-rabbit antibody coupled
to alkaline phosphatase (DAKO) before substrate development as
described above.
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Results and Discussion |
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). N-type cell lines that have high tumorigenic indices in
nude mice (10)
were also resistant to TRAIL-induced cell
death. In contrast, noninvasive S-type cells were extremely sensitive
to TRAIL-induced cell death, even at doses as low as 1 ng/ml (Fig. 1B
).
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). Down-regulation of
surface Fas expression has been described for other cancers
(16)
and may be a common mechanism of resistance to
Fas-mediated apoptosis used by tumor cells. In contrast, TRAIL
receptors could be detected on all cell types; S-type cells expressed
mRNA specific for TRAIL-R1, TRAIL-R2, and TRAIL-R3, whereas N-type
cells expressed only TRAIL-R2 mRNA (Fig. 1C
). TRAIL-R4 mRNA
was not detected in any of the cell lines, although RT-PCR of control
TRAIL-R4 cDNA gave a positive signal (data not shown). FACS analysis
demonstrated very high levels of surface TRAIL-R2 on S-type cells,
whereas N-type cells expressed slightly lower levels that were
comparable with TRAIL-R2 expression by Jurkat T cells (Fig. 1D
). The findings that S-type cells express surface Fas and
TRAIL receptors but are uniquely sensitive to TRAIL suggest that the
Fas pathway is not functional in these cells. The lack of decoy
receptor mRNA expression in N-type cells excluded the possibility that
TRAIL-R3 or TRAIL-R4 was responsible for N-type cell resistance to
TRAIL.
Expression of signaling molecules downstream of TRAIL death receptors
was then examined. Caspase-3, caspase-8, and caspase-10 are involved in
both Fas- and TRAIL-mediated apoptosis, with cFLIP being a negative
regulator of both pathways. Adaptor potein FADD is essential for
Fas-mediated cell death (17)
and TRAIL-R2-mediated cell
death (18)
. Both Jurkat T cells and S-type NB cells
expressed cFLIP mRNA, whereas no cFLIP mRNA could be detected in N-type
cells (Fig. 2A
). It is unlikely that cFLIP inhibits TRAIL-mediated
apoptosis in S-type cells because they undergo extensive cell death at
low doses of TRAIL. In contrast, cFLIP may contribute to the
resistance of S-type cells to Fas-mediated apoptosis because its
expression is known to be more crucial in reducing sensitivity to
Fas-induced cell death than reduced levels of Fas on the cell surface
(7
, 19) . Expression of FADD and of caspases-3 and -10 was
detected by Western blotting in both S-type and N-type cells at levels
comparable to those in Jurkat T cells (Fig. 2B
).
Surprisingly, neither caspase-8 mRNA nor protein was present in N-type
cells, although they were readily detectable in S-type cells (Fig. 2 and B
).
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). In contrast,
caspase-3 was not cleaved after incubation with TRAIL in N-type LAN-1
cells that do not express caspase-8. In agreement with these findings,
caspase-3 activity after TRAIL treatment was found only in S-type cells
(Fig. 2D
). No caspase-10 processing was observed in either
cell type (data not shown). Caspase-8 is essential for the initiation
of the Fas and TNF apoptotic pathways (20)
, and we propose
that it is also important for TRAIL-induced cell death in NB cells
because caspase-8 cleavage occurs soon after the addition of TRAIL in
S-type cells and coincides with caspase-3 cleavage and activation. We
tested a total of 11 NB cell lines (4 S-type and 7 N-type cell lines)
for TRAIL sensitivity and caspase-8 expression, and we found that all
S-type cell lines expressed caspase-8 and were sensitive to TRAIL,
whereas all N-type cell lines did not express caspase-8 and were TRAIL
resistant (data not shown). The amplification of the N-MYC
oncogene in these cell lines did not correlate with down-regulation of
caspase-8 expression or TRAIL resistance, suggesting that
N-MYC is not involved in this phenomenon.
The in vivo expression of caspase-8 by malignant NB tumors
was investigated by immunocytochemistry comparing a malignant NB stage
IV tumor with a benign ganglioneuroma (Fig. 3C
). The expression of N-CAM, a neural adhesion molecule that
is strongly expressed by NB and related neuroectoderm-derived tumors
(21)
, and the MHC class I molecules (HLA-I), which are
lacking in late-stage NB tumor cells (11)
, is also shown
(Fig. 3 and B
). Sections of ganglioneuroma
gave homogeneously positive stainings for N-CAM, HLA-I, and caspase-8.
The malignant NB stage IV tumor was positive for N-CAM and negative for
HLA-I and expressed only low levels of caspase-8, whereas regions of
normal cells surrounding the tumor were observed to be N-CAM negative
and HLA-I and caspase-8 positive. Therefore, as observed for N-type NB
cells, caspase-8 expression appears to be reduced in late-stage NB
tumors. In contrast, more differentiated ganglioneuromas are similar to
S-type cells in that they express both caspase-8 and HLA-I. The fact
that a subset of malignant NB tumors down-regulates the expression of
caspase-8, which is a key initiator of death receptor-mediated
apoptosis, could explain their highly aggressive behavior and thei
resistance to most treatment regimens (1)
. Whereas our
study is the first to provide evidence that caspase-8 expression is
absent in aggressive neuroblastomas, lower levels of caspase-1 and -3
have been measured in high-stage NB tumors, compared with those of
lower stages (22)
. In addition to the absence of HLA-I,
the down-regulation of caspase expression could therefore be a general
mechanism used by NB cells to evade immune attack.
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A), as has been described previously (15)
.
Genomic DNA derived from one localized stage II tumor sample and two
stage IV tumor samples digested with EcoRI was also
investigated for the presence of caspase-8. In all tumor samples,
polymorphic fragments of 4 and 8 kb hybridized to the caspase-8 probe
(Fig. 4B
). Because no large homozygous deletions were
detected in the caspase-8 gene, it seemed more likely that
the absence of expression was due to the inhibition of caspase-8 mRNA
synthesis. Indeed, incubation of N-type SH-SY5Y cells for 24 h
with 3 µM AzaC, a demethylating agent, induced
the expression of caspase-8 protein (Fig. 4C
). This suggests
that the caspase-8 promoter is hypermethylated, a mechanism of gene
regulation that has been proposed for the down-regulation of Fas
expression by oncogenic Ras (16)
. Treatment with AzaC
induced cell death in SH-SY5Y cells (Fig. 4D
), probably as a
result of the expression caspase-8 or other methylated genes. However,
preincubation of SH-SY5Y cells with AzaC did enhance their sensitivity
to TRAIL-mediated cell death, suggesting that caspase-8 expression is
required for the TRAIL pathway to function in NB cells.
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FOOTNOTES |
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1 Supported by grants from the Antoine Leenaards
Foundation, the Swiss National Scientific Foundation, and the
FORCE Foundation. 
2 To whom requests for reprints should be
addressed, at Department of Pediatric Onco-Hematology, Centre
Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland.
Phone: 021-314-3622; Fax: 021-314-3558; E-mail: ngross{at}chuv.hospvd.ch
3 The abbreviations used are: NB, human
neuroblastoma; TRAIL, tumor necrosis factor-related apoptosis-inducing
ligand; TNF, tumor necrosis factor; RT-PCR, reverse transcription-PCR;
MAb, monoclonal antibody; FACS, fluorescence-activated cell-sorting;
AzaC, 5-aza-2'-deoxycytidine; c-Flip, cellular Flice inhibitory
protein; FasL, Fas ligand; N-CAM, neural cell adhesion molecule; HLA-I,
class I molecules.
Received 3/17/00. Accepted 6/28/00.
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), 100 ng/ml anti-Fas MAb
(
), or 100 ng/ml cross-linked soluble TRAIL (
). Tests were
performed in quadruplicate, and means and SDs were calculated.
B, percentage of cell viability of S-type cell lines
SH-EP (
), and CA-2-E (
) and N-type cell line LAN-1
(
