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Tumor Biology |
Institut National de la Santé et de la Recherche Médicale U517, Facultés de Médicine et de Pharmacie, 21033 Dijon Cédex, France
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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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The broad expression of TRAIL and its inability to induce
apoptosis in normal cells suggested that the regulation of
TRAIL-induced cell death was through restricted receptor expression.
Two distinct receptors for TRAIL, designated TRAIL-R1 (or DR4; Ref.
9
) and TRAIL-R2 (or DR5; Refs. 10, 11, 12, 13
), were
identified. Both are type I transmembrane proteins and contain a death
domain similar to that of Fas and TNF-R1 in their cytoplasmic
COOH-terminal portions. Their mRNA is expressed in many of the same
normal tissues as TRAIL. Two additional receptors for TRAIL designated
TRAIL-R3 (or DcR1/TRID; Refs. 10
, 11,
and 14
)
and TRAIL-R4 (or DcR2; Refs. 15, 16, 17
) differ from TRAIL-R1
and TRAIL-R2 by their cytoplasmic domains. TRAIL-R3 is devoid of any
transmembrane or cytoplasmic domain and is
glycosylphosphatidylinositol-linked to the cell surface, whereas
TRAIL-R4 contains only a partial death domain. These two receptors are
capable of binding TRAIL with an affinity comparable with that of
TRAIL-R1 and TRAIL-R2 (14
, 15)
but do not mediate
apoptosis upon ligation. Thus, TRAIL-R3 and TRAIL-R4 were proposed to
act as decoy receptors and to determine whether a cell is resistant or
sensitive to TRAIL. In addition, ligation of TRAIL-R4 was suggested to
increase the antiapoptotic threshold of cells by activating the
transcription factor nuclear factor-
B (15)
. However,
the expression of TRAIL receptor mRNAs does not correlate with cell
sensitivity to TRAIL (3)
, and the ligation of TRAIL-R1 and
TRAIL-R2 also results in the activation of nuclear factor-B,
although still resulting in apoptosis (12
, 18)
.
Alternative hypotheses for the differential sensitivity of normal and tumor cells to TRAIL include the differential expression of intracellular inhibitors of apoptosis or expression and subcellular location of the death receptors (19) . The death signaling pathway through TRAIL-R1 and TRAIL-R2 was shown recently to involve the recruitment of the adaptor molecule FADD in a death-inducing signaling complex (20, 21, 22) . In turn, FADD recruits procaspase-8 in the death-inducing signaling complex through homophilic interactions between death effector domains contained in the NH2-terminus of FADD and the prodomain of these caspases (23 , 24) . Caspase-8 is activated and triggers cell death, either by directly activating downstream effector caspases such as caspase-3 and caspase-6 (25 , 26) or by cleaving Bid, a BH3 domain-containing proapoptotic member of the Bcl-2 family of proteins that activates the mitochondrial pathway to cell death (27) . These two FADD-dependent cell death pathways can be inhibited by expression of c-FLIP (also called Casper/I-FLICE/FLAME-1/CASH/CLARP/MRIT/Usurpin), a protein with a structure similar to that of caspase-8 but lacking a catalytic site and competitively interacting with FADD, caspase-8, and possibly caspase-10 (28) . The expression of c-FLIP was proposed recently to be an essential determinant of cell sensitivity to TRAIL (29) .
Several genotoxic agents were reported to up-regulate the expression of TRAIL-R1 and TRAIL-R2 mRNAs by both p53-dependent and independent mechanisms (30, 31, 32, 33) . This up-regulation was proposed to account for the synergistic activity of TRAIL and chemotherapeutic drugs described in several tumor cell lines (34 , 35) . In the present study, we compared the sensitivity of four human colon cancer cell lines to TRAIL, and we examined the apoptosis sensitization of the most resistant cell lines to soluble TRAIL by the cytotoxic drugs cisplatin and doxorubicin.
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MATERIALS AND METHODS |
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Chemicals and Antibodies.
The cytotoxic drugs cisplatin and doxorubicin were obtained from Roger
Bellon Chemical Co. (Neuilly, France) and Sigma-Aldrich (Saint-Quentin
Fallavier, France), respectively. The caspase inhibitors z-VAD-fmk,
z-IETD-fmk, z-DEVD-fmk were from Calbiochem (San Diego, CA). mAbs
raised against TRAIL-R1 (M271, IgG2a), TRAIL-R2 (M413, IgG1), TRAIL-R3
(M430, IgG1), and TRAIL-R4 (M445, IgG1) were kindly provided by Dr. M.
Kubin (Immunex Corp., Seattle, WA), whereas the blocking mAb RIK2
(IgG1) raised against human TRAIL was a kind gift of Dr. H. Yagita
(Juntendo University, Tokyo, Japan). Neutralizing polyclonal goat Abs
raised against extracellular domains of TRAIL-R1 and TRAIL-R2 were
obtained from R&D Systems (Abingdon, United Kingdom). Mouse IgG1 and
IgG2a (Dako Corp., Carpinteria, CA) and goat IgG (Jackson
ImmunoResearch Labs, Beckman Coulter, Villepinte, France) were
used as isotype-matched controls. The recombinant human soluble TRAIL
contains a Flag sequence and can be cross-linked by an enhancer (an
antibody anti-Flag); these reagents were obtained from Alexis
Biochemicals (Coger, Paris, France). We also used mouse mAbs raised
against human procaspase-8 from Immunotech (Coulter, Marseille,
France), human HSC70 from Santa Cruz (Tebu, Le Perray en Yvelines,
France), Flag (M2) from Sigma-Aldrich, rabbit polyclonal Abs raised
against human Bid from R&D Systems, and human Bid from Dr. X. Wang
(Howard Hughes Medical Institute, Dallas, TX). All other chemicals were
of reagent grade and purchased from local sources.
Flow Cytometry Analyses.
The expression of TRAIL-R1 through TRAIL-R4 was studied in the
different colon cancer cell lines by flow cytometry after
trypsinization. Appropriate concentrations of mAbs were added to the
cells in 100 µl of PBS containing 0.5% BSA (PBS-BSA) and 0.1%
sodium azide (Sigma-Aldrich). After 1-h incubation at 4°C and two
washes in PBS, cells were incubated for 45 min at 4°C with a
FITC-conjugated sheep antimouse IgG (Amersham, Les Ulis, France). These
experiments were repeated on cells fixed in 4% paraformaldehyde and
permeabilized in saponin (0.1% v/v in PBS-BSA). In all cases, 10,000
cells were analyzed by using a FACScan flow cytometer (Becton
Dickinson).
Western Blot Analyses.
For immunoblotting, untreated and treated cells were washed in PBS and
lysed for 10 min at 4°C in lysis boiling buffer [1% SDS, 10
mM Tris (pH 7.4)] and boiled for 5 min. Proteins (50 µg)
were separated on a polyacrylamide SDS-containing gel and transferred
to a polyvinylidene difluoride membrane (Bio-Rad, Ivry sur Seine,
France). After blocking nonspecific binding sites overnight at 4°C by
8% nonfat milk in TPBS (PBS with 0.1% Tween 20), membranes were
incubated for 2 h at room temperature with specific Abs. Membranes
were then washed twice with TPBS and incubated further at room
temperature for 1 h with horseradish peroxidase-conjugated goat
antimouse or antirabbit Ab (Jackson ImmunoResearch Laboratories).
Membranes were washed twice with TPBS and revealed using an enhanced
chemiluminescence detection kit (Amersham).
Measurement of Caspase Activities.
Untreated and treated cells were lysed in lysis buffer [10
mM HEPES (pH 7), 40 mM sodium glycerophosphate,
50 mM NaCl, 2 mM MgCl2,
and 5 mM EGTA] and then incubated for 1 h at 37°C
in a caspase assay buffer [100 mM HEPES (pH 7.4), 10%
glycerol, 0.5 mM EDTA, 0.05% BSA, and 1 mM
DTT] containing 20 µM IETD-AFC or DEVD-AMC (Calbiochem).
Caspase activities were measured by monitoring fluorescence
continuously in a dual luminescence fluorimeter (LS 50B Perkin-Elmer,
Courtaboeuf, France) using specific excitation and emission
wavelengths for IETD-AFC and DEVD-AMC peptide derivative substrates,
respectively. Enzyme activities were determined as initial velocities
and expressed as relative intensity/min/mg.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The level of expression of the two receptors was similar
in each individual cell line. This level of expression differed from
one cell line to another, with HCT116 cells expressing the highest
level and HT29 cells expressing the lowest level of both proteins. In
contrast, the two decoy receptors TRAIL-R3 and TRAIL-R4 were not
detected at the cell surface of the four cell lines (for example see
results obtained in HT29 cells; Fig. 1B
), whereas the tested
mAbs could detect these receptors at the cell surface of K562 human
leukemic cells (not shown). Because mRNAs encoding these two proteins
could be detected in the four cell lines using reverse
transcription-PCR (not shown), we further looked at their expression in
the studied cells after permeabilization of the plasma membrane with
saponin. As demonstrated on Fig. 1C
, TRAIL-R3 and TRAIL-R4
were identified in the four cell lines after permeabilization.
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, cell sensitivity to TRAIL correlated with the expression
of TRAIL-R1 and TRAIL-R2 on their plasma membrane, with HT29 cells
being the most resistant and HCT116 cells being the most sensitive to
TRAIL-induced cytotoxicity (Fig. 1A)
. The cytotoxic activity
of TRAIL was found to be related to its ability to trigger apoptotic
cell death (Fig. 2B)
. The specificity of TRAIL-induced
apoptosis was demonstrated in HCT116 cells by showing its inhibition in
the presence of the neutralizing mAb RIK-2 directed against human TRAIL
(Fig. 3)
. Both TRAIL-R1 and TRAIL-R2 are required for TRAIL-delivered cell
death signal because a combination of neutralizing goat Abs directed
against the extracellular domain of each receptor is required to
completely inhibit TRAIL-induced colon carcinoma apoptosis, whereas
each Ab tested alone only partially inhibits cell death induced by the
cytokine (Fig. 3)
.
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). At concentrations ranging from 0.86 to 8.6 µM
for doxorubicin or from 8 to 16 µM for cisplatin, the two
cytotoxic agents demonstrated a limited cytotoxic effect on the three
tested cell lines. As shown on Fig. 4
, TRAIL-induced cytotoxicity was significantly enhanced by cotreatment
with low concentrations of either doxorubicin or cisplatin. This effect
was the most obvious in HT29 cells that were the most resistant cells
to TRAIL used alone. Morphological studies indicated that cytotoxic
drugs enhanced TRAIL-mediated apoptosis that was inhibited by the
neutralizing monoclonal antibody RIK-2 (data not shown) and the caspase
inhibitors z-VAD-fmk, z-DEVD-fmk, and z-IETD-fmk (for example, see the
results obtained on HT29 cells exposed to doxorubicin in Fig. 5
).
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, neither doxorubicin (0.86 or 8.6 µM for 24 h) nor
cisplatin (8 or 16 µM for 24 h) significantly
increased the expression of TRAIL-R1 and TRAIL-R2 on the plasma
membrane of the three studied cell lines. We also observed that these
cytotoxic agents had no effect on the expression of TRAIL-R3 or
TRAIL-R4 examined in permeabilized cells (data not shown).
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. In accordance with the cleavage of procaspase-8 and PARP, the use of
peptide substrates that mimic the target cleavage site of caspase-8
(IETD-AFC) and caspase-3 or caspase-7 (DEVD-AMC) demonstrated that
cytotoxic drugs increased the ability of TRAIL to activate these
caspases in the two studied colon cancer cell lines (Fig. 8)
.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Identification of TRAIL decoy receptors that bind TRAIL with comparable affinity (<1 nM) to TRAIL-R1 and TRAIL-R2 (14 , 15) but do not mediate apoptosis upon ligation because of the lack (TRAIL-R3) or truncation (TRAIL-R4) of their cytoplasmic domains initially suggested that expression of these receptors might be a key determinant of cell sensitivity to TRAIL-induced cell death (3 , 10 , 11 , 14, 15, 16) . Then, it was observed that several tumor cell lines that were sensitive to TRAIL actually expressed TRAIL-R3 and TRAIL-R4 mRNA when studied by reverse transcription-PCR or RNase protection assay (3 , 15 , 33) . However, mRNA expression does not reflect cell-surface expression of the proteins (37) . In the present study, although we detected the four receptor mRNAs in the four studied cell lines (not shown), only TRAIL-R1 and TRAIL-R2 could be detected at the cell surface of these cell lines. Permeabilization of the plasma membrane was required to detect the two decoy receptors, even in the most resistant HT29 cells. Thus, neither TRAIL-R3 nor TRAIL-R4 might significantly influence colon cancer cell line sensitivity to TRAIL. In contrast, the spontaneous sensitivity of the four studied colon cancer cell lines was observed to correlate with the level of expression of the two death receptors TRAIL-R1 and TRAIL-R2 at the cell surface. Both receptors are required for TRAIL to mediate a maximal cell death signal. A fifth receptor to TRAIL, osteoprotegerin, which exists in a secreted form and competitively inhibits TRAIL binding to TRAIL-R1 and TRAIL-R2 (38) , was proposed to modulate the sensitivity of melanoma cell lines to TRAIL-induced cell death (37) . Because the mRNA encoding osteoprotegerin could not be detected in HT29 cells (39) , this receptor might not account for the resistance of HT29 cells to TRAIL-induced apoptosis.
Several recent reports described the ability of subtoxic concentrations of chemotherapeutic drugs to sensitize tumor cells that are resistant to TRAIL (33, 34, 35 , 40) . The synergistic cytotoxic effect of genotoxic drugs and TRAIL, which was observed also in multidrug-resistant cell lines (35 , 40) and was confirmed in our study, was proposed to be mediated by a transcriptional induction of TRAIL-R1 and TRAIL-R2 (30, 31, 32, 33) and to be p53 dependent (30 , 32) . Up-regulation of TRAIL-R1 and TRAIL-R2 has been studied previously either at the mRNA level (30, 31, 32, 33) and by immunoblotting (33) . This drug-induced up-regulation was not confirmed in the present study in which the expression of both receptors was analyzed at the plasma membrane by flow cytometry. This lack of modulation of TRAIL receptor membrane expression upon exposure to DNA-damaging agents did not depend on p53 status because it was observed in both p53 wild-type and p53-mutated cell lines.
The concentration of cytotoxic drugs used to sensitize tumor cells to TRAIL-induced cell death could account for the discrepancies we observed with other studies. High concentrations of etoposide that are not clinically relevant were shown to up-regulate TRAIL-R1 and TRAIL-R2 mRNA and protein levels in breast cancer cell lines (33) , whereas lower, more clinically relevant concentrations of doxorubicin had no effect on the expression of the studied receptors in these cell lines (34) . Thus, we cannot rule out that higher concentrations of doxorubicin or cisplatin could have enhanced the expression of TRAIL receptors at the surface of the tested colon carcinoma cells. Discrepancies between studies could also depend on the choice of the cytotoxic drug because low concentrations of doxorubicin were shown to sensitize breast cancer cells to TRAIL, whereas high concentrations of 5-fluorouracil were required for obtaining this effect (34) .
We have shown previously that the cytotoxic drugs doxorubicin and cisplatin were able to increase the expression of another death receptor, Fas (CD95/APO-1), at the surface of HT29 cells (36) . This up-regulation was shown to account for drug-induced sensitization of colon cancer cells to Fas-mediated cell death. The present study indicates that the molecular mechanisms of drug-induced sensitization to TRAIL might be distinct from those of drug-mediated sensitization to Fas agonists. In addition, although a role for Fas in drug-induced cytotoxicity has been established (41) , the role of TRAIL receptors in chemotherapeutic drug-mediated cytotoxicity remains to be investigated.
The differential expression of intracellular inhibitors of apoptosis is another mechanism that could account for the differential sensitivity of colon carcinoma cell lines to TRAIL-mediated apoptosis. One of the molecules that can interfere with TRAIL-mediated cell death is c-FLIP (9 , 29 , 42) , a protein structurally related to procaspase-8 but lacking a catalytic active site and the residues that form the substrate binding pocket (28) . This protein, which was implicated in the resistance of resting T cells to Fas-induced cell death (43) and in the progression and immune escape of tumors in vivo (44 , 45) , is predominantly found as a Mr 55,000 isoform in most tissues and cell lines (46) , although a minor species of Mr 27,000/28,000 was also detected in some cell types (28 , 47) . The level of c-FLIP expression decreases upon exposure to actinomycin D, which was proposed to account for cell sensitization to TRAIL-induced apoptosis by this inhibitor of transcription (37) . In colon cancer cell lines, we did not identify any correlation between c-FLIP expression, as determined by immunoblotting, and spontaneous cell sensitivity to TRAIL nor cell sensitization to TRAIL-mediated cell death by the chemotherapeutic agents doxorubicin and cisplatin (not shown).
Interestingly, cytotoxic drugs lowered the signaling threshold required for TRAIL-induced cell death. Both doxorubicin and cisplatin sensitized colon cancer cells to TRAIL-induced cleavage of procaspase-8 and PARP and caspase activation. These results indicated that anticancer drugs increased the ability of TRAIL to trigger a caspase-dependent cell death, in accordance with observations made in breast cancer cells and described previously (34) . Fas-mediated cell death can involve the cleavage of the COOH-terminal part of a BH3 domain-containing proapoptotic member of the Bcl-2 family designated Bid. Then, translocation of the truncated Bid to mitochondria causes various changes, leading to the activation of effector caspases (48 , 49) . In accordance with a recent report (27) , we show here that similar events are involved in TRAIL-mediated apoptosis. Although they do not seem to modulate the expression of Bid in colon cancer cells, the cytotoxic drugs doxorubicin and cisplatin sensitize these cells to TRAIL-mediated decreased expression of the native form of Bid in its p15 fragment and the activation of effector caspases that cleave PARP (26) .
The safety of TRAIL administered in vivo to athymic mice either locoregionally (50) or i.v. (5 , 6) and its efficacy in suppressing tumor growth suggested that TRAIL-based tumor therapy may be an efficient anticancer strategy. The ability of subtoxic concentrations of chemotherapeutic drugs to restore TRAIL-mediated pathway to death in cell lines that are resistant to TRAIL-induced cytotoxicity (34 , 35) suggested that combination of an anticancer drug with TRAIL may enforce the TRAIL-based therapeutic strategy. The present study shows that clinically relevant concentrations of genotoxic agents lower the signaling threshold required for TRAIL-induced cell death without increasing the expression of TRAIL receptors. Interestingly, the cytotoxic drugs tested in this study have limited efficacy toward colon cancer cells by themselves, whereas their combination with TRAIL is an effective inducer of tumor cell death in vitro. It remains to be determined whether this combination increases the selectivity of anticancer therapy toward tumor cells in vivo, as suggested by initial studies testing the combination of TRAIL to 5-fluorouracil (5) . Confirmation of the clinical interest of this strategy would be of great importance in colon cancer cells that remain highly resistant to most chemotherapeutic drugs used alone.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by grants from the comités de la
Nièvre (to M. T. D. B.), de Bourgogne (to E. S.), de la Ligue
Nationale Contre le Cancer (to S. L.), and from Association Regionale
pour l’Enseignement et la Recherche Scientifique-Champagne
Ardennes (to E. S.). The E. S. group is called "La
Ligue." 
2 To whom requests for reprints should be
addressed, at INSERM U517, Faculties of Medicine and Pharmacy, 7
Boulevard Jeanne d’Arc, 21033, Dijon Cédex, France. Phone:
(33) 3 80 39 32 84; Fax: (33) 3 80 39 34 34; E-mail: mtboitre{at}u-bourgogne.fr
3 The abbreviations used are: TRAIL, tumor
necrosis factor-related apoptosis-inducing ligand; TNF, tumor necrosis
factor; mAb, monoclonal antibody; FADD, Fas-associated death domain;
z-VAD-fmk, z-Val-Ala-Asp-fluoromethyl ketone; z-IETD-fmk,
z-Ile-Glu-Thr-Asp-fluoromethylketone; z-DEVD-fmk,
z-Asp-Glu-Val-Asp-fluoromethylketone; IETD-AFC,
IETD-7-amino-4-tri-fluoromethylcoumarine; DEVD-AMC,
DEVD-7-aminomethylcourmarine; PARP, poly(ADP-ribose)
polymerase.
Received 4/13/00. Accepted 12/27/00.
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B.. Immunity, 7: 831-836, 1997.[Medline]
B and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain.. Immunity, 7: 813-820, 1997.[Medline]
B pathway.. Immunity, 7: 821-830, 1997.[Medline]
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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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J. Asakuma, M. Sumitomo, T. Asano, T. Asano, and M. Hayakawa Selective Akt Inactivation and Tumor Necrosis Factor-related Apoptosis-inducing Ligand Sensitization of Renal Cancer Cells by Low Concentrations of Paclitaxel Cancer Res., March 15, 2003; 63(6): 1365 - 1370. [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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A. B. Werner, E. de Vries, S. W. G. Tait, I. Bontjer, and J. Borst TRAIL Receptor and CD95 Signal to Mitochondria via FADD, Caspase-8/10, Bid, and Bax but Differentially Regulate Events Downstream from Truncated Bid J. Biol. Chem., October 18, 2002; 277(43): 40760 - 40767. [Abstract] [Full Text] [PDF]
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Q. Wang, X. Wang, A. Hernandez, M. R. Hellmich, Z. Gatalica, and B. M. Evers Regulation of TRAIL Expression by the Phosphatidylinositol 3-Kinase/Akt/GSK-3 Pathway in Human Colon Cancer Cells J. Biol. Chem., September 20, 2002; 277(39): 36602 - 36610. [Abstract] [Full Text] [PDF]
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T. Ohtsuka and T. Zhou Bisindolylmaleimide VIII Enhances DR5-mediated Apoptosis through the MKK4/JNK/p38 Kinase and the Mitochondrial Pathways J. Biol. Chem., August 2, 2002; 277(32): 29294 - 29303. [Abstract] [Full Text] [PDF]
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M. A. Eid, R. W. Lewis, and M. V. Kumar Mifepristone Pretreatment Overcomes Resistance of Prostate Cancer Cells to Tumor Necrosis Factor {alpha}-related Apoptosis-inducing Ligand (TRAIL) Mol. Cancer Ther., August 1, 2002; 1(10): 831 - 840. [Abstract] [Full Text] [PDF]
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