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Tumor Biology |
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
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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 induces apoptosis by interacting with two death domain-containing death receptors DR4 (also known as TRAIL-R1) and DR5 (also called TRAIL-R2, TRICK2, and KILLER/DR5; Refs. 5 and 8 ). TRAIL signaling involves recruitment of caspase-8 or caspase-10 via Fas-associated death domain or an unknown adaptor protein and activation of the caspase cascade, resulting in apoptotic cell death (5 , 8) . TRAIL can also bind to three decoy receptors, DcR1 (TRAIL-R3 or TRID), DcR2 (TRAIL-R4 or TRUNDD), and OPG, that contain either no cytoplasmic death domain or truncated death domain and can compete with DR4 and DR5 for ligand binding, thereby acting as an antagonist (5 , 8) . TRAIL and its receptors DR4 and DR5 are expressed widely in both normal and malignant cells, whereas DcR1 and DcR2 are expressed preferentially in many normal tissues but in only a few transformed cells (5 , 8) . Therefore, it was suggested that the low toxicity of TRAIL toward normal tissues is attributable to the expression of decoy receptors in normal tissues, which can protect normal cells from induction of apoptosis by TRAIL (5 , 8) .
TRAIL-induced apoptosis was suggested to be independent of p53 (5 , 9) . Likewise, p53-independent induction of DR5 expression was observed (10, 11, 12) . However, TRAIL signaling may be related to p53 because DR5 can be regulated by p53 (10 , 13, 14, 15) and can be increased by p53-elevating DNA-damaging agents in tight association with induction of apoptosis (10 , 13 , 16 , 17) . Thus, it is plausible to assume that agents, which up-regulate the expression of death receptors DR4, DR5, or both, will augment TRAIL-induced apoptosis. Indeed, chemotherapeutic agents such as DOX, 5-Fu, VP-16, and CPT-11 show synergy in apoptosis induction when combined with TRAIL in certain types of cancer cell both in vitro and in vivo (18, 19, 20) . The molecular mechanism underlying the enhanced efficacy of these combinations is not well understood.
The synthetic retinoid CD437 is a potent inducer of apoptosis in a variety of cancer cell types including human breast cancer (21) , melanoma cells (22) , cervical cancer (23) , leukemia (24) , and NSCLC (25, 26, 27) cells. In previous studies, we have demonstrated that CD437 induces apoptosis in human NSCLC cells through both p53-dependent and p53-independent pathways (16 , 28) . CD437 increased the level of p53 protein and subsequently induced the expression of p53-regulated genes such as Bax, p21 (WAF1/CIP1), and DR5, which eventually triggered apoptosis through induction of cytochrome c release from mitochondria and caspase-3 activation (16 , 28) .
Because CD437 induces DR5 expression in a p53-dependent manner in human NSCLC cells (16) , we hypothesized that CD437 may augment TRAIL-induced apoptosis in human NSCLC cells, particularly those with wild-type p53. To test this hypothesis, we examined the effects of CD437 and TRAIL combination on apoptosis induction in human NSCLC cell lines. This combination exhibited more than additive induction of apoptosis, which was p53 dependent.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Lines and Cell Culture.
Human NSCLC cell lines H460, A549, and H1944, which possess wild-type
p53, and NSCLC cell lines H596, H157, and H1792, which express mutant
or no p53 (29)
, were either obtained from Dr. A. Gazdar
(University of Texas Southwestern Medical Center, Dallas, TX) or
purchased from the American Type Cell Culture (Rockville, MD). H460
cell lines transfected with either Neo or HPV-16 E6 as described
previously (16)
was obtained from Dr. W. S. El-Deiry
(University of Pennsylvania School of Medicine, Philadelphia, PA).
These cells were grown in monolayer culture in a 1:1 (v/v) mixture of
DMEM and Ham’s F-12 medium supplemented with 5% fetal bovine serum
and antibiotics at 37°C in a humidified atmosphere consisting of 5%
CO2 and 95% air. In addition, we also used
normal human NHBE and SAEC cells, which were purchased from Clonetics
(San Diego, CA). These cells were grown in BEGM BulletKit (Clonetics)
at 37°C in a humidified atmosphere consisting of 5%
CO2 and 95% air.
Northern Blot Analysis.
Preparation of total cellular RNA and the Northern blotting were
described previously (30)
. Thirty µg of total RNA were
loaded in each lane. Human Killer/DR5 cDNA was obtained from Dr. W. S.
El-Deiry. Human Bax cDNA was provided by Dr. S. J. Korsmeyer
(Washington University School of Medical, Saint Louis, MO). Human DR4,
DcR1, and DcR2 cDNAs were purchased from Alexis Biochemicals. Human
glyceraldehyde-3-phosphate dehydrogenase cDNA was purchased from
Ambion, Inc. (Austin, TX).
Western Blot Analysis.
Preparation of whole-cell lysates and the Western blotting were
described previously (28)
. Fifty µg of protein were
loaded in each lane. Mouse monoclonal anti-Bcl-2 (100), rabbit
polyclonal anti-Bcl-XS/L (S-18), and goat
polyclonal anti-Bid (C-20) antibodies were purchased from Santa Cruz
Biotechnology, Inc. (Santa Cruz, CA). Rabbit polyclonal anti-Bax
antibody, mouse anti-caspase-3 (clone 19), mouse monoclonal
anti-caspase-7 (clone B94-1), mouse monoclonal anti-cytochrome
c (clone 7H8.2C12), and mouse monoclonal anti-caspase-9
(clone B40) antibodies were purchased from PharMingen (San Diego, CA).
Mouse monoclonal anti-caspase-8 (clone 5F7), rabbit polyclonal
anti-caspase-10, and rabbit polyclonal anti-DFF45 antibodies were
purchased from Upstate Biotechnology (Lake Placid, NY). Rabbit
polyclonal PARP antibody (VIC 5) and rabbit polyclonal ß-actin
antibody were purchased from Roche Molecular Biochemicals
(Indianapolis, IN) and Sigma, respectively.
DNA Fragmentation Assay.
Cells were plated in 96-well cell culture plates or 10-cm-diameter
dishes 1 day before treatment. After 24 h treatment, DNA
fragmentation was evaluated by examination of cytoplasmic
histone-associated DNA fragments (mono- and oligonucleosomes) using a
Cell Death Detection ELISAPlus kit (Roche
Molecular Biochemicals) according to the manufacturer’s instructions.
In addition, DNA fragments with 3'-hydroxyl ends were quantitated using
an APO-DIRECT TUNEL kit (Phoenix Flow Systems, Inc., San Diego, CA)
following the manufacturer’s protocol.
Measurement of Cytochrome c Release.
Cells were plated onto 10-cm-diameter dishes 1 day before treatment.
After the cells were exposed to CD437 for the indicated time, both
floating and attached cells were harvested, and cytosolic extracts were
prepared as described previously (16)
.
Measurement of Caspase Activity.
Cells were plated onto 10-cm-diameter dishes 1 day before treatment.
After the cells were exposed to CD437 for different times, both
floating and attached cells were harvested by trypsinization and
counted. Caspase activity was measured as described by Deveraux
et al. (31)
. The fluorogenic substrate
Ac-Asp-Glu-Val-Asp-AFC (for caspase-3), Ac-Ile-Glu-Thr-Asp-AFC (for
caspase-8), and Ac-Leu-Glu-His-Asp-AFC (for caspase-9) were used,
respectively.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and
B, this combination caused additive or more than additive
induction of apoptosis evidenced by the ELISA method. The lowest
concentrations of CD437 and TRAIL required for this effect were 0.1
µM and 5 ng/ml, respectively. This finding was
confirmed by the TUNEL-flow cytometric apoptosis assay (Fig. 1C)
. At a concentration of 0.2 µM,
CD437 enhanced TRAIL-induced apoptosis, whereas several
chemotherapeutics agents including CDDP, VP-16, 5-FU, and DOX used at
the same concentration did not enhance induction of apoptosis when
combined with 10 ng/ml TRAIL in the H460 cells (Fig. 1D)
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A, CD437 at 0.2
µM indeed induced the expression of both death
receptors. TRAIL itself neither induced nor enhanced the effect of
CD437 on the expression of these genes. DcR1 and DcR2 mRNAs were
neither detected in H460 cells nor induced by CD437 or CD437 plus TRAIL
(data not shown). CD437 did not change Bax expression (data not shown).
Soluble rhOPG:Fc or rhDcR2:Fc abolished the augmented induction of
apoptosis by the CD437 and TRAIL combination in H460 cells (Fig. 2B)
. Taken together, these results indicate that enhanced
induction of apoptosis by combination of CD437 and TRAIL is
attributable to the up-regulation of DR4 and DR5 by CD437.
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, even when the
concentration of CD437 was increased to 0.5 µM
in the cell lines with mutant p53 (data not show). Furthermore, the
augmented induction of apoptosis by the CD437 and TRAIL
combination, which was observed in H460 cells transfected with
Neo control gene, was not observed in H460 cells transfected
with HPV-16 E6 gene, in which p53 protein has been degraded
(Fig. 3B)
. These results further support the conclusion that
the interaction between CD437 and TRAIL in apoptosis induction in human
NSCLC cells is dependent on p53 status.
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C, each of the
agents induced apoptosis in H460 cells but not in the two types of
normal human lung epithelial cells (i.e., NHBE and SAEC).
Furthermore, the combination of CD437 and TRAIL induced more than
additive effects on H460 but not on normal cells, indicating that the
combination targets lung cancer cells selectively.
Involvement of Caspases in Augmented Induction of Apoptosis by
CD437 and TRAIL Combination.
Caspase activation is known to be a critical event in signaling death
receptor-mediated apoptotic pathway (5)
. To determine
which caspases are involved in apoptosis induced by the combination of
CD437 and TRAIL, we analyzed their effects on the pattern of caspase
activation in H460 cells. CD437 and TRAIL alone did not activate or
only slightly activated the initiator caspases caspase-8 and caspase-9.
However, the combination of CD437 and TRAIL resulted in activation of
both caspases, as evidenced by their auto-cleavage (activation; Fig. 4A
). The enhanced activation
of these two caspases by the combination was also reflected by
measuring caspase-8 and especially caspase-9 activity (Fig. 4B)
. The combination of CD437 and TRAIL did not activate
caspase-10 because no cleavage was detected. A similar analysis of
effector caspases revealed that the combination of CD437 and TRAIL
resulted in enhanced cleavage of both caspase-3 and caspase-7 and the
subsequent cleavage of their substrates PARP and DFF45 (Fig. 4C)
. Caspase-3 activity was also enhanced in cells treated
with the combination relative to each agent alone (Fig. 4D)
.
The enhanced induction of apoptosis by the combination of CD437 and
TRAIL could be blocked by the pan caspase inhibitor Z-VAD-FMK, the
caspase-3 inhibitor Z-DEVD-FMK, the caspase-8 inhibitor Z-IETD, and the
caspase-9 inhibitor Z-LEHD-FMK, respectively (Fig. 5)
. Taken together, these results
demonstrate that initiator caspases caspase-8 and caspase-9 and
effector caspases caspase-3 and caspase-7 are involved in mediating the
augmented induction of apoptosis by the CD437 and TRAIL combination.
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, treatment of H460 cells with the CD437
and TRAIL combination resulted in enhanced cytochrome c
release compared with CD437 or TRAIL alone, which only weakly induced
cytochrome c release.
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. Because Bid
can be activated through cleavage by caspase-8 during apoptosis
(34
, 35) , it is possible that the decrease in the level of
Bid in the cells treated with CD437 and TRAIL combination is
attributable to its cleavage by caspase-8.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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TRAIL-induced apoptosis has been reported to be independent of p53 (5 , 9) . Likewise, the sensitization of human breast cancer cells to TRAIL-induced apoptosis by chemotherapeutic agents such as DOX and VP-16 were independent of p53 status (18 , 19) . However, the TRAIL receptor DR5 is regulated by p53 (10 , 13, 14, 15) . We found that augmentation of TRAIL-induced apoptosis by CD437 in human NSCLC cells was dependent on wild-type p53 as evidenced by the findings that the effect was observed only in human NSCLC cell lines carrying wild-type p53 and that targeting degradation of wild-type p53 protein by HPV-16 E6 abolished the interaction between CD437 and TRAIL on apoptosis induction in H460 cells. These results were consistent with our previous study that indicated that CD437 induces DR5 expression in a p53-dependent manner in human NSCLC cells (16) . A recent study also showed a p53-dependent augmentation of TRAIL-induced apoptosis by radiation through up-regulation of DR5 in human breast cancer cells (36) . It should be pointed out that the role of p53 in augmentation of TRAIL-induced apoptosis by CD437 might be dependent on cell types. Recently, we found that CD437 augmented TRAIL-induced apoptosis independently of p53 status in human prostate cancer cells (12) .
The combination of CD437 and TRAIL failed to induce apoptosis in two normal human lung epithelial cells derived either from bronchus (NHBE) or from small airway (SAEC) in short-term culture, despite their presumed wild-type p53 status. This finding is important from a clinical point of view because it implies that the CD437 and TRAIL combination may selectively kill cancers while sparing normal cells. Although the mechanism of this selectivity is not known, it could be attributable to differences in expression levels of decoy receptors or different regulation of death receptors by CD437 in lung cancer cells and normal lung epithelial cells.
Caspases play important roles in apoptosis triggered by various proapoptotic signals (37 , 38) . Ligation of death ligands (e.g., Fas ligand) with their receptors activates the caspase cascade, leading to apoptosis through adaptor molecules (5 , 8) . In general, activation of the caspase cascade requires both initiator caspases, such as caspase-8, caspase-9, and caspase-10, and effector caspases such as caspase-3 and caspase-7. Caspase-3 and caspase-7 cleave several key substrates such as PARP and DFF45, leading to apoptosis (37 , 38) . Currently, it is less clear which and how initiator caspases are activated during TRAIL receptor-triggered apoptosis (5 , 8) . We found that the combination of CD437 and TRAIL resulted in activation of caspase-3 and caspase-7 and the cleavage of their substrates PARP and DFF45. Moreover, the pan caspase inhibitor Z-VAD-FMK and the caspase-3 inhibitor Z-DEVD-FMK suppressed apoptosis induced by the combination of CD437 and TRAIL. Therefore, it appears that caspase-3 and caspase-7 mediate apoptosis induced by the combination of CD437 and TRAIL. In addition, we found that the combination of CD437 and TRAIL activated caspase-8 and caspase-9 but not caspase-10, and that caspase-8 and caspase-9 inhibitors blocked apoptosis by this combination. These results indicate that caspase-8 and caspase-9, rather than caspase-10, are the initiator caspases involved in the caspase cascade leading to apoptosis by the combination of CD437 and TRAIL.
It is well known that both caspase-8 and caspase-9 can activate caspase-3 and caspase-7 in response to different death signals (37 , 38) . Caspase-8 is thought to mediate apoptosis signaled by death receptors such as Fas, whereas caspase-9 is thought to mediate apoptosis triggered by signals such as chemotherapeutic agents (37, 38, 39) . However, possible cross-talk between caspase-8- and caspase-9mediated apoptotic pathways may exist. Recent studies indicate that Bid, a Bcl- 2 interacting protein that is activated (truncated) by caspase-8, can bridge these two pathways by mediating death receptor-triggered cytochrome c release from mitochondria (34 , 35 , 40) . However, it is not clear whether this is also true for TRAIL-induced apoptosis. In our study, we found that the combination of CD437 and TRAIL not only activated caspase-9 but also induced cytochrome c release from mitochondria. Cytochrome c released from mitochondria binds to Apaf-1, thereby triggering Apaf-1-mediated activation of caspase-9 (41) . Therefore, our results suggest that the combination of CD437 and TRAIL can activate the cytochrome c/caspase-9-mediated apoptotic pathway. The question remains how this pathway is activated by ligation of TRAIL and its receptors. Our study demonstrated that the combination of CD437 and TRAIL increased the cleavage of Bid but did not change the level of Bcl-2 family proteins Bcl-2, Bax, and Bcl-XL. This suggests that the combination of CD437 and TRAIL can activate receptor-mediated cytochrome c/caspase-9-apoptotic pathway through the activation of Bid.
In summary, we found that CD437 can augment TRAIL-induced apoptosis by CD437 through p53-dependent up-regulation of death receptors DR4 and DR5 in human NSCLC cells. Moreover, we provide evidence indicating the involvement of caspase-8, caspase-9, caspase-7, and caspase-3 in this effect. Our results also suggest a potential strategy of using CD437 in combination with TRAIL for prevention or treatment of certain lung cancers.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This study was supported by The University of
Texas M. D. Anderson Cancer Center Institutional Research Grant, by
USPHS Grant U19 CA68437 from the National Cancer Institute, and by the
Tobacco Settlement Funds as appropriated by the Texas State
Legislature. W. K. H. is an American Cancer Society Clinical Research
Professor. R. L. is the incumbent of the Irving and Nadine Mansfield
and Robert David Levitt Cancer Research Chair. 
2 To whom requests for reprints should be
addressed, at Department of Thoracic/Head and Neck Medical Oncology,
Box 80, The University of Texas M. D. Anderson Cancer Center, 1515
Holcombe Boulevard, Houston, TX 77030. Phone: (713) 745-5062; Fax:
(713) 794-0209; E-mail: ssun{at}mdanderson.org
3 The abbreviations used are: TRAIL, tumor
necrosis factor-related apoptosis-inducing ligand; CD437,
6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid;
OPG, osteoprotegerin; PARP, poly(ADP-ribose) polymerase; rh,
recombinant human; Z-VAD-FMK, Z-Val-Ala-Asp-fluoromethyl ketone;
Z-DEVD-FMK, Z-Asp-Glu-Val-Asp-FMK; Z-IETD-FMK,
Z-lle-Glu(OMe)-Thr-Asp(OMe)-FMK; Z-LEHD-FMK,
Z-Leu-Glu(OMe)-His-Asp(OMe)-FMK; CDDP, cisplatin; VP-16, etoposide;
5-FU, 5-fluorouracil; DOX, doxorubicin; NSCLC, non-small cell lung
carcinoma; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP
nick end labeling; NHBE, normal human bronchial epithelial; SAEC, small
airway epithelial cell; HPV, human papillomavirus; DFF, DNA
fragmentation factor; Ac, acetyl; AFC,
7-amino-4-(trifluoromethyl)-coumaride.
Received 5/10/00. Accepted 10/12/00.
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REFERENCES |
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