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Biochemistry and Biophysics |
Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612 [R. Y., S. M., A-N. T. K.], and Human Genome Sciences, Rockville, Maryland 20850 [S. R., J. N.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(TNF-) is ineffective unless in the presence of
the protein synthesis inhibitor cycloheximide. The induction of
apoptosis by TRAIL in PC-3 cells was mediated by a death receptor, DR
4, and the downstream caspases. Treatment of PC-3 cells with TRAIL also
activated c-Jun NH2-terminal kinase 1 (JNK1); however,
inhibition of JNK1 activation by its dominant-negative mutant had
little effect on TRAIL-induced apoptosis. Furthermore, TRAIL weakly
stimulated nuclear factor 
B activity in PC-3 cells. Interestingly,
activation of nuclear factor B pathway by pretreatment with TNF-
did not prevent the induction of apoptosis by TRAIL. These data
indicate that TRAIL triggers apoptosis in advanced prostate cancer
cells through the activation of caspase cascades, which appears to be
independent of TNF-- and JNK-mediated mechanisms. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(9)
. Unfortunately, use of these apoptosis-inducing agents
has been limited by their unacceptable systemic toxicity. Thus, the
challenge today is to identify or develop a cytotoxic agent that
selectively induces apoptosis in metastatic prostate cancer cells but
avoids significant toxicity to the normal tissues.
TRAIL (also called Apo-2L) is a type II transmembrane protein that was
initially identified by searching an expressed sequence tag database
with the most conserved extracellular sequence of TNF family (10
, 11)
. Human TRAIL consists of 281 amino acids and shows highest
homology with FasL (28%), followed by TNF (23%), and LT
(23%). The transcripts of TRAIL have been detected in many human
tissues such as spleen, thymus, prostate, and lung (10
, 11)
. To date, at least five receptors for human TRAIL have been
identified, including DR4 (12)
, DR5 (also called Apo-2,
TRAIL-R2, TRICK2, or KILLER; Refs. 13, 14
), DcR1 (also
called TRID, TRAIL-R3, or LIT; Refs. 15, 16
), DcR2
(also called TRAIL-R4 or TRUNDD; Ref. 17
), and TR1
(18)
. Ligation of TRAIL to DR4 or DR5 induces
trimerization of the receptor, which further interacts with downstream
death domain-containing adapter proteins leading to the activation of
caspases (cysteine-dependent aspartate-directed proteases) and
apo-ptotic cell death (19)
. In contrast to DR4 and
DR5, DcR1 and DcR2 contain an incomplete cytoplasmic death domain and
have been reported to prevent TRAIL-induced apoptosis, presumably by
competing with DR4 and DR5 for binding to TRAIL (15, 16, 17)
.
Similar to TNF and FasL, TRAIL induces apoptosis in a wide variety of
transformed or cancerous cells (10
, 11)
. However, unlike
TNF and FasL, TRAIL shows little cytotoxicity to the normal cells
(10)
. Most interestingly, in contrast to the severe
inflammatory response syndrome induced by systemically administered TNF
and the fulminant hepatotoxicity of FasL, administration of TRAIL to
mice seems to be devoid of systemic toxicity but shows antitumor
activity (20)
. Thus, TRAIL may be a new promising
candidate for treatment of cancer.
To explore the potential of TRAIL for treatment of advanced prostate
cancer, we examined apoptosis and the signaling events in TRAIL-treated
androgen-independent prostate cancer cells. Our results showed that
treatment of PC-3 and DU145 cells with TRAIL caused rapid apoptosis
that was mediated by DR4 and downstream caspases but seemed to be
independent of JNK and NFB pathways.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and caspase inhibitors z-VAD-fmk,
Ac-DEVD-CHO, and z-IETD-fmk were purchased from CalBiochem (La Jolla,
CA). CHX was purchased from Sigma Chemical Co. (St. Louis, MO).
Preparation of Soluble TRAIL.
A PCR fragment encoding soluble FLAG-TRAIL (amino acids 95–281) was
cloned into the His-tag vector pET15b (12)
. The construct
was then transformed into Escherichia coli BL21 (DE3)
competent cells (Novagen, Madison, WI). His-FLAG-TRAIL recombinant
protein was purified from bacterial lysates by using nickel chalet
affinity chromatography. The concentration of purified protein was
determined by the Bradford method (Bio-Rad, Hercules, CA) using BSA as
standard. The purity of samples was assessed by electrophoresis.
Analysis of Apoptosis.
After treatments, floating cells were collected by centrifugation at
1000 x g for 5 min, and attached cells were
first trypsinized and then harvested by centrifugation. Apoptotic cells
were assayed by using annexin-V-FITC staining kit (PharMingen, San
Diego, CA). Briefly, the harvested cells were washed twice with
ice-cold PBS and resuspended in a binding buffer containing both
annexin-V-FITC and propidium iodide. After incubation at room
temperature for 15 min, samples were analyzed by FACScan. Apoptosis was
presented as the percentage of cells stained positive for
annexin-V-FITC but negative for propidium iodide.
Reverse Transcription-PCR Analysis of TRAIL Receptor Expression.
Total RNA was extracted with TRIzol reagent. cDNA was synthesized by
using the SuperScript Preamplification System (Life Technologies, Inc.,
Gaithersburg, MD) and treated with 0.1 unit/µl E. coli
RNase H at 37°C for 20 min. PCR was performed in a 50-µl reaction
mixture containing cDNA (derived from 50 ng of total RNA), 1 unit of
Taq DNA polymerase, 10 mM Tris-HCl (pH 8.3), 50
mM KCl, 1.5 mM
MgCl2, 200 µM
deoxynucleotide triphosphate (each), and 200 ng/µl of each primer.
Amplification was run for 35 cycles, with each cycle of PCR consisting
of 1 min of denaturation at 94°C, 1 min of annealing at 60°C, and 2
min of extension at 72°C. PCR products were analyzed by agarose gel
(1.5%) electrophoresis and photographed under UV light. Nucleotide
sequences of PCR primers (23)
used were as follows: DR4,
5'-CTG AGC AAC GCA GAC TCG CTG TCC AC-3' (sense), 5'-TCA AAG GAC ACG
GCA GAG CCT GTG CCA T-3' (antisense); DR5, 5'-ATG GAA CAA CGG GGA CAG
AAC-3' (sense), 5'-TTA GGA CAT GGC GTC TGC ATT AC-3' (antisense); DcR1,
5'-ACC CTA AAG TTC GTC GTC GTC ATC-3' (sense), 5'-TCA AAC AAA CAC AAT
CAG AAG CAC-3' (antisense); and DcR2, 5'-CTT TTC CGG CGG CGT TCA TGT
CCT TC-3' (sense), 5'-GTT TCT TCC AGG CTG CTT CCC TTT GTA G-3'
(antisense). RT-PCR analysis of
ß2-microglobulin was described previously
(24)
.
Caspase Activity Assay.
After TRAIL treatment, cells were washed twice with ice-cold
phosphate-buffed saline and lysed in a buffer containing 50
mM Tris-HCl (pH 7.4), 50 mM
ß-glycerophosphate, 15 mM MgCl2, 15
mM EDTA, 100 mM phenylmethylsulfonyl fluoride,
1 mM DTT, and 150 mg/ml digitonin. After being left on ice
for 30 min, cell lysates were passed through a 23-gauge needle three
times and cleared by centrifugation. Caspase activity was determined by
fluorogenic assays described previously (25)
.
Immunocomplex Kinase Assay of JNK1 Activity.
After TRAIL stimulation, cells (in a 60-mm plate) were washed twice
with ice-cold phosphate-buffered saline and lysed in a 250-µl buffer
containing 10 mM Tris-HCl (pH 7.1), 50 mM NaCl,
50 mM NaF, 100 µM
Na3VO4, 30 mM
Na4P2O7,
5 µM ZnCl2, 2 mM
iodoacetic acid, 1 mM phenylmethylsulfonyl fluoride, and
0.5% Triton X-100. Cell lysates were homogenized by passing through a
23-gauge needle three times before incubation on ice for 30 min.
Homogenates were cleared by centrifugation at 12,500 x g for 20 min and were assayed for JNK1 activity by using
immunocomplex kinase assays described previously (22)
.
Preparation of Nuclear Extracts and Electrophoretic Mobility
Shift Assay.
Nuclear extracts of PC-3 (106 cells) were
prepared as described previously (26)
. For each binding
reaction, 10 µg of nuclear protein, as determined by the Bradford
method (Bio-Rad), were incubated with 1 ng of labeled, double-stranded
NFB oligonucleotide (
70,000 cpm) in a 10-µl binding buffer
containing 0.5 µg poly(deoxyinosinic-deoxycytidylic acid), 9%
glycerol, 10 mM HEPES (pH 7.9), 60 mM KCl, 1
mM EDTA, and 1 mM DTT at room temperature for
30 min. The resulting DNA-protein complexes were resolved in a 5%
nondenaturing polyacrylamide gel at 5 W in Tris/glycine buffer (pH
8.4). The gel was dried and autoradiographed. NFB binding
oligonucleotide (sense, 5'-AGT TGA GGG GAC TTT CCC AGG C-3'; antisense,
5'-GCC TGG GAA AGT CCC CTC AAC T-3'; Promega Corp., Madison, WI) was
labeled at the 5' end with [
-32P]ATP using
T4 kinase (Life Technologies, Inc.). The labeled oligonucleotides were
purified by passing through a G-25 column. Competition analysis was
performed by adding a 25-fold molar excess amount of unlabeled NFB
oligonucleotides.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Induces Apoptosis in PC-3 and DU145 Cells.
. The induction of apoptosis became evident after 6 h
of treatment with 50 ng/ml of TRAIL and reached 70% when TRAIL
concentration increased to 200 ng/ml. In contrast, little cell death
was observed in the cells treated with increasing concentrations of
TNF- for 36 h (Fig. 1A)
. However, PC-3 cells became
sensitive to TNF- killing in the presence of CHX (2
µM). Interestingly, pretreatment with CHX had
little effect on TRAIL-induced apoptosis. Similar results were obtained
when DU145 cells were treated with TRAIL and TNF- in the presence or
absence of CHX (Fig. 1B)
.
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, TRAIL (100 ng/ml) stimulated DEVD- and IETD-specific
activities in a time-dependent manner. In contrast, little
YVAD-specific activity was observed over the same time period. Further
time course study (as shown inside Fig. 2A
) revealed that
the induction of IETD-specific activity was early and preceded the
induction of DEVD-specific activity, consistent with the notion that
caspase-8 activity is upstream of caspase-3-like proteases in
DR-mediated apoptosis.
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, z-VAD-fmk, a general inhibitor of caspases, blocked
TRAIL-induced cell death in a dose-dependent manner. At a concentration
of 25 µM, z-VAD-fmk completely abolished
apoptosis. Pretreatment with z-IETD-fmk, a specific inhibitor of
caspase-8, and Ac-DEVD-CHO, a specific inhibitor of caspase-3-like
proteases, also significantly inhibited TRAIL-induced apoptosis in a
dose-dependent fashion. Thus, TRAIL induces apoptosis in PC-3 cells
through a caspase-dependent mechanism.
TRAIL-induced Apoptosis in PC-3 Cells Is Mediated by DR4.
TRAIL has been shown to be able to induce cell death through DR4, DR5,
or both, depending on the expression of these DRs in the target cells.
To identify TRAIL receptors that are responsible for the induction of
apoptosis in PC-3 cells, we conducted reverse transcription-PCR
analysis. A strong cDNA band derived from DR4 mRNA was observed,
whereas DR5, DcR1, and DcR2 mRNA transcripts were undetectable (Fig. 3A)
. To exclude the possibility that the failure of detection
of DR5, DcR1, and DcR2 mRNAs was attributable to the use of improper
primers or unfavorable PCR conditions, we repeated the experiment with
different primers or under different conditions. Again, no band was
observed. Thus, the PC-3 cell line seems to selectively express DR4.
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, when overexpressed, DR4 induced apoptosis in a
dose-dependent manner. The addition of z-VAD-fmk (25
µM) completely blocked this induction. Thus,
overexpressed DR4 was able to mimic TRAIL to induce caspase-dependent
apoptosis.
TRAIL Stimulates JNK1 Activity, Which Appears to Be Independent of
Caspases and Apoptosis.
In addition to the activation of caspases, cross-linking of DRs by
TNF- or FasL also has been shown to initiate kinase cascades,
leading to the activation of JNK (29)
. To examine whether
TRAIL is able to activate this pathway, we treated PC-3 cells with
TRAIL for different time periods. As determined by immunocomplex kinase
assays, TRAIL stimulated JNK1 activity, which occurred 1 h after
treatment and reached a maximum at 3 h (Fig. 4A)
. Interestingly, the activation of JNK1 by TRAIL appears to
be modest, with a maximum of 4-fold induction over control being
observed.
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and 4A)
, we next examined whether JNK1 activation by TRAIL
depends on caspases. PC-3 cells were treated with the different
concentrations of caspase inhibitor, z-VAD-fmk or Ac-DEVD-CHO, prior to
the challenge with TRAIL. Neither z-VAD-fmk nor Ac-DEVD-CHO inhibited
JNK1 activation by TRAIL (Fig. 4B)
. Instead, pretreatment
with z-VAD-fmk slightly enhanced TRAIL-induced JNK1 activity. These
data suggest that activation of JNK1 by TRAIL is independent of
caspases.
A Dominant-Negative Mutant of JNK1 Inhibits JNK1 Activation by
TRAIL But Does Not Affect Apoptosis.
Given the fact that TRAIL-induced apoptosis is completely blocked in
the presence of 25 µM z-VAD-fmk whereas TRAIL-induced
JNK1 activity is intact, we speculate that JNK1 activation may not be
essential for the induction of apoptosis by TRAIL. To test this
hypothesis, we used JNK1(APF), a dominant-negative mutant of JNK1,
which has been shown previously to inhibit apoptosis induced by
-radiation (21)
and UVB (30)
. As shown in
Fig. 5A
, overexpression of JNK1(APF) inhibited TRAIL-induced JNK1
activity in a dose-dependent fashion. However, inhibition of JNK1
activation by JNK1(APF) had little effect on TRAIL-induced apoptosis,
as determined by annexin-V-FITC staining (Fig. 5B)
.
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B Activity in PC-3 Cells.B (19)
. Accordingly, we asked
whether TRAIL is able to activate the NFB pathway. As measured by
electrophoretic mobility shift assay, TRAIL induced a detectable NFB
binding activity at 1 and 3 h (Fig. 6A)
. However, under similar conditions, TNF- induced a huge
shift band. Thus, compared with TNF-, TRAIL stimulated a weaker
NFB activity in PC-3 cells.
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B pathway may prevent cell
death induced by death ligands and cancer chemotherapy drugs (31
, 32)
. Strong activation of NFB by TNF- may therefore
provide a reasonable explanation for the resistance of these prostate
cancer cells to TNF-. To test whether TNF--induced NFB
activation confers cross-resistance to TRAIL-induced apoptosis, we
pretreated PC-3 cells with TNF- prior to stimulation with TRAIL.
Regardless of the duration of TNF- treatment, no significant effect
was observed on the induction of apoptosis by TRAIL (Fig. 6B)
, suggesting that distinct signaling components were
involved in cell death induced by TRAIL and TNF-. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although we have observed a strong activation of DEVDases or caspase-3-like proteases, we were unable to detect any significant changes in the activity of YVADases or caspase-1-like proteases, the caspases that have been shown to directly activate caspase-3 in vitro (33) . This raises the possibility that caspases other than caspase-1-like proteases are involved in the activation of caspase-3-like proteases. Previous studies with FasL- or TNF-induced apoptosis indicate that cross-linking of Fas or TNF receptors results in the recruitment of death domain-containing proteins (FADD/MORT1) that, in turn, interact with caspases such as caspase-8, thereby initiating a caspase cascade (19) . Indeed, treatment of PC-3 cells with TRAIL induced caspase-8 activity, and z-IETD-fmk, an inhibitor of caspase-8, attenuated TRAIL-induced apoptosis, implicating the important role of this caspase. Whether the activation of caspase-8 by TRAIL involves a FADD-dependent mechanism is currently not clear. A recent report shows that cells from FADD-deficient mice are resistant to apoptosis induced by Fas, TNFR1, and DR3 but show full responsiveness to DR4, which supports the existence of a FADD-independent pathway that couples TRAIL to caspases (34) . However, transfection studies with the dominant-negative FADD have yielded conflicting results (12 , 13) . Thus, elucidation of adapter protein(s) for TRAIL receptors warrants further studies.
JNK, also called stress-activated protein kinase, is a member of the
mitogen-activated protein kinase family (35)
. A number of
studies have identified JNK to be involved in the regulation of
apoptosis. Activation of JNK has been shown to be required for the
induction of apoptosis by stress stimuli such as growth factor
withdrawal (36)
, -radiation, and UVC (21)
.
However, the role of JNK pathway in receptor-induced apoptosis seems to
vary depending on the nature of DRs and the cell lines. For example, in
Jurkat cells, anti-Fas (CH-11) strongly induces caspase-dependent
activation of JNK1, which seems to be dispensable for Fas-mediated
apoptosis (21
, 37)
, whereas in 293 and HeLa cells, JNK
activation by FasL is essential for the induction of apoptosis
(38)
. With respect to TNF signaling, JNK activation has
been dissociated with the FADD-mediated apoptotic pathway
(39)
. In this study, we demonstrated that TRAIL was
capable of activating the JNK signaling pathway, which appeared to be
independent of caspases, as indicated by the delayed activation pattern
and the lack of effects of caspase inhibitors. However, direct
interference with JNK1 activity by overexpression of a
dominant-negative mutant of JNK1 did not affect the induction of
apoptosis by TRAIL. Consistent with this observation, a recent study
also indicates that, although TRAIL can activate JNK through both
caspase-dependent and caspase-independent pathways, activation of JNK
may not be sufficient for the induction of apoptosis (40)
.
Therefore, we conclude that activation of JNK pathway may not be
directly involved in the induction of apo-ptosis by TRAIL.
NFB is a transcription factor that plays an important role in
immunological and inflammatory responses by inducing a number of
proinflammatory cytokine genes. Recent reports suggest that NFB is
also involved in the regulation of apoptosis (31)
.
Activation of NFB has been demonstrated to suppress the induction of
apoptosis by a variety of apoptotic agents, including certain routinely
used anticancer drugs (32)
, and thereby may counteract
their therapeutic efficacy. NFB activation is also believed to
contribute to the severe inflammatory response syndrome after systemic
administration of certain TNF- doses. We observed that, in PC-3
cells, TNF- strongly induced NFB activity but failed to induce
apoptosis unless in the presence of protein synthesis inhibitor,
supporting the view that activation of NFB may induce antiapoptotic
genes and protect cells against TNF--induced apoptosis. However,
unlike TNF-, TRAIL only weakly induces NFB activity, as shown in
this study as well as by others (12
, 16)
. Most
interestingly, activation of NFB by pretreatment with TNF- has
little effect on the induction of apoptosis by TRAIL (Fig. 6B)
, suggesting that distinct pathways may exist in
regulating TRAIL-induced apoptosis. Alternatively, the differential
effects of NFB on TRAIL- and TNF--induced apoptosis may reflect
the different natures of their receptors to recruit the
antiapo-ptotic proteins, the expression of which is under the
control of NFB because the NFB-stimulated inhibitory effect on
TNF--induced apoptosis often occurs at the level of receptor complex
(41)
. Future elucidation of TRAIL receptor-associated
proteins will shed light on this issue.
In summary, this study demonstrates that TRAIL induces massive
apoptotic cell death in androgen-independent prostate cancer cells. The
induction of apoptosis is mediated by caspase cascades. Although TRAIL
also activates JNK1 and, to a lesser extent, stimulates NFB
activity, modulation of these pathways has no significant effect on
TRAIL-induced apoptosis. Furthermore, the induction of apoptosis by
TRAIL is independent of p53 because PC-3 cells do not express
functional p53 (42)
. Thus, TRAIL may have therapeutic
potential against advanced prostate cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by University of Illinois at
Chicago Functional Food. 
2 To whom requests for reprints should be
addressed, at Department of Pharmaceutics and Pharmacodynamics, Center
for Pharmaceutical Biotechnology MC870, College of Pharmacy, University
of Illinois at Chicago, 900 South Ashland Avenue, MBRB, Room 3102,
Chicago, IL 60607-7173. Phone: (312) 413-9646; Fax: (312) 413-9303;
E-mail: KongT{at}uic.edu
3 The abbreviations used are: FasL, Fas ligand;
TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing
ligand; NFB, nuclear factor B; JNK, c-Jun
NH2-terminal kinase; DR, death receptor; DcR, decoy
receptor; CHX, cycloheximide; GST, glutathione
S-transferase; z-VAD-fmk,
benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone; Ac-DEVD-CHO,
acetyl-Asp-Glu-Val-Asp-aldehyde; z-IETD-fmk,
benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethyl ketone; FADD,
Fas-associated death domain.
Received 10/29/99. Accepted 3/ 6/00.
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A. F. Taghiyev, N. V. Guseva, H. Harada, C. M. Knudson, O. W. Rokhlin, and M. B. Cohen Overexpression of BAD Potentiates Sensitivity to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Treatment in the Prostatic Carcinoma Cell Line LNCaP Mol. Cancer Res., May 1, 2003; 1(7): 500 - 507. [Abstract] [Full Text] [PDF]
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 V. Poulaki, C. S. Mitsiades, V. Kotoula, S. Tseleni-Balafouta, A. Ashkenazi, D. A. Koutras, and N. Mitsiades Regulation of Apo2L/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Thyroid Carcinoma Cells Am. J. Pathol., August 1, 2002; 161(2): 643 - 654. [Abstract] [Full Text] [PDF]
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M. 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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 M. Fu, C. Wang, J. Wang, X. Zhang, T. Sakamaki, Y. G. Yeung, C. Chang, T. Hopp, S. A. W. Fuqua, E. Jaffray, et al. Androgen Receptor Acetylation Governs trans Activation and MEKK1-Induced Apoptosis without Affecting In Vitro Sumoylation and trans-Repression Function Mol. Cell. Biol., May 15, 2002; 22(10): 3373 - 3388. [Abstract] [Full Text] [PDF]
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I. Holen, P. I. Croucher, F. C. Hamdy, and C. L. Eaton Osteoprotegerin (OPG) Is a Survival Factor for Human Prostate Cancer Cells Cancer Res., March 1, 2002; 62(6): 1619 - 1623. [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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