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Molecular Oncology, Markers, Clinical Correlates |
The Burnham Institute, La Jolla, California 92037 [I. T., S. K., K. W., S. K., J. C. R.]; University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 [S. M. K., H. S., Y. H. Q., M. A.]; and National Cancer Institute, Developmental Therapeutics Program, Frederick Cancer Research and Development Center, Frederick, Maryland [D. A. S., G. T., A. M.]
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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 IAPs4 are a family of antiapoptotic proteins that are conserved across evolution, with homologues found in both vertebrate and invertebrate animal species (5) . The baculovirus IAPs, Cp-IAP and Op-IAP, were the first members of this family to be identified based on their ability to functionally complement defects in the cell death inhibitor, p35, a baculovirus protein that binds to and inhibits caspase-family cell death proteases (6 , 7) . Subsequently, five human (XIAP, cIAP1, cIAP2, NAIP, and Survivin) and two Drosophila IAP homologues have been identified, which have been demonstrated to inhibit cell death (4 , 8, 9, 10, 11, 12, 13, 14) . The human IAPs, XIAP, cIAP1, and cIAP2, have been reported to bind and potently inhibit caspase-3 and caspase-7 with Kis in the range of 0.2–10 nM (15 , 16) . These IAP-inhibitable caspases operate in the distal portions of apoptotic protease cascades, functioning typically as effectors rather than initiators of apoptosis (17, 18, 19) . Although quantitative studies are lacking, the IAP-family member Survivin also binds and inhibits some effector caspases (14 , 20) . Moreover, at least some IAPs, such as XIAP, are capable of binding and suppressing specific initiator caspases such as caspase-9, the pinnacle caspase in the cytochrome c/mitochondrial pathway for apoptosis (21) .
The common structural feature of all IAP family members is an 
70
amino acid zinc-binding fold termed the BIR domain, which is present in
one to three copies (22)
. Using a mutagenesis approach, we
showed previously that the second of the three BIR domains (BIR2) of
XIAP is necessary and sufficient for inhibiting the effector caspase-3
and caspase-7 (23)
, implying that a single BIR domain can
possess antiapoptotic activity. However, for caspase-9 suppression by
XIAP, the third BIR domain is required (24)
.
To learn more about the importance of IAPs in cancer and leukemia, we examined the expression of several members of the IAP family in the well-characterized NCI panel of 60 human tumor cell lines, correlating their expression at either the mRNA or protein levels with other tumor-related genes and with in vitro chemosensitivity data for 30,000 compounds. In addition, the prognostic significance of one of the IAPs, XIAP, was examined in AML, revealing correlations with clinical outcome, thus suggesting that analysis of IAP-family proteins may provide predictive information about responses to chemotherapy and survival for at least some subgroups of patients with AML.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Immunoblot Analysis of AML Samples.
Immunoblotting of AML patient samples derived from 78 newly diagnosed
patients with AML and 10 normal individuals was carried out using cell
lysates from mononuclear fractions of peripheral blood generated by
Ficoll separation. Whole-cell lysates from 5 x 105
cells were electrophoresed through 8–14% SDS-PAGE gradient gels and
electroblotted to Immobilon polyvinylidene difluoride membranes
(Millipore, Bedford, MA) using a semi-dry transfer apparatus at 0.8
mA/cm2 for 1.5 h (25)
. Each gel included
a XIAP-expressing positive control cell line (HeLa), two to three
peripheral blood mononuclear cell samples from normal individuals, and
molecular weight markers. The membranes were blocked in Tris-buffered
saline with 0.05% Tween 20 (TBST) and 3% nonfat dry milk (Blotto) at
4°C for 4 h and then exposed overnight to a mouse anti-XIAP
monoclonal antibody (Pharmingen, San Diego, CA) at a 1:350 dilution at
4°C overnight. Subsequently, the membranes were washed twice in
Blotto, exposed to sheep antimouse IgG conjugated to horseradish
peroxidase (1:4000) for 1 h, washed in Blotto and TBST, and then
exposed to SuperSignal West Pico substrate chemiluminescence mixture
for 1 min according to the directions of the manufacturer (Pierce
Corp., Rockford, IL). Images were collected on a ChemiImager 4400
system (Alpha Innotech, San Leandro, CA), and densitometry was
performed using the best image. To normalize for variation in antibody
concentration or time of exposure, the XIAP signal from the patient was
normalized against the XIAP signal of the control cell line HeLa.
Results are expressed in terms of this ratio.
Immunoblot Analysis of Tumor Cell Lines.
Detergent lysates were prepared in the presence of protease inhibitors
from established tumor cell lines essentially as described
(26)
. After normalization for total protein content (50
µg/lane), samples were subjected to SDS-PAGE/immunoblot analysis
using monoclonal anti-IAP antibodies specific for XIAP (Transduction
Laboratories, Lexington, KY) or for cIAP1 and cIAP2 (R&D Systems,
Minneapolis, MN). Data on X-ray films were quantified by scanning
densitometry using the IS-1000 image analysis system (Alpha Innotech
Co.), and the results from a standard curve generated using purified
recombinant GST-XIAP, GST-cIAP1, or GST-cIAP2 protein were used to
estimate the amounts (ng) of XIAP, cIAP1, and cIAP2 protein per 50 µg
of total protein. Data from two independent protein standard-containing
blots were within 10% agreement.
RNase Protection Assays.
Total RNA was isolated from the NCI 60 tumor cell line panel or freshly
isolated AML cells using the RNeasy Mini kit (Qiagen, Germany),
according to the manufacturer’s manual. After normalization for total
mRNA content (12 µg/lane), samples were subjected to RPA, as
described in the manufacturer’s manual (Riboquant; Pharmingen, La
Jolla, CA). Briefly, a multiprobe was used for the T7
polymerase-directed synthesis of a 32P-labeled antisense
RNA probe set. The probe set was hybridized in excess to target RNA in
solution, after which free-probe and other single-stranded RNA were
digested with RNases. The remaining "RNase-protected" probes were
purified, resolved on denaturing polyacrylamide gels (4.75%), and
quantified by autoradiography and phosphorimaging (Bio-Rad
Laboratories, Inc.; Molecular Analyst, Version 2.1). The quantity of
each mRNA species in the original RNA sample was then determined based
on the intensity of the appropriately sized, protected probe fragment
relative to the loading control (GAPDH).
Statistical Analysis.
Comparison of IAP mRNA and protein levels with chemosensitivity data
for the 60 cell line panel (NCI) resulted in a rank order of drugs from
the standard agent database of the NCI. Pearson correlation
coefficients and two-tail Ps were used to assign possible
significance to these data. P 
0.005 was considered
significant in all analyses.
For analysis of patient data, results were rank-ordered according to
XIAP protein levels and divided into thirds, thus assessing possible
threshold effects of XIAP on survival while avoiding searching for
optimal cutpoints for levels of XIAP (27)
. The top
two-thirds demonstrated similar outcomes, and therefore those arms were
collapsed. Unadjusted survival analyses were performed using
Kaplan-Meier plots (28)
, and comparisons of survival
between patient subgroups were made using the log-rank test
(29)
. For comparisons of clinical variables between
patients within the lowest third of XIAP expression versus
the top two-thirds, either Student’s t test or
2 analysis was performed. All computations were
performed using Statistica version 5.1 M (StatSoft Inc., Tulsa, OK).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. GAPDH was included as a
control to ensure equal loading. Data on X-ray films were quantified by
scanning densitometry (Fig. 2)
. The mRNAs
for XIAP and cIAP1 were detectable at variable levels in all cell lines
analyzed (Fig. 2, A and B)
. In contrast, cIAP2
was more restricted in its expression. cIAP2 mRNA was abundant, for
example, in most CNS and many renal tumor cell lines but almost
undetectable in ovarian and breast cancer lines (Fig. 2C)
.
Thus, in contrast to XIAP and cIAP1 mRNAs that were present in all
tumor lines, the presence of cIAP2 mRNA was detectable in only 34
(56%) of the 60 tumor cell lines within the NCI screening panel. NAIP
mRNA was undetectable in the entire panel of 60 tumor cell lines but
was plentiful in some normal tissues, such as peripheral blood
lymphocytes (not shown).
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Higher levels of XIAP
protein were generally found in renal cancer and melanoma cell lines,
whereas lower levels of XIAP were typically present in CNS tumor cell
lines (Fig. 3B)
. cIAP1 protein was expressed at higher
levels in colon cancers, whereas lower levels were found in melanoma
cell lines
. The expression of cIAP2 was far more
restricted; cIAP2 protein was detectable in only 5 (8%) of the 60
tumor cell lines analyzed (MCF7, HT29, A549, NCI H322M, and K562).
Thus, protein data for cIAP2 did not correlate with mRNA data.
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and
3B
). Conversely, XIAP mRNA levels were below the mean of
tumor cell lines in the leukemia lines K562 and MOLT4, the lung cancer
line HOP-62, the colon cancer line KM12, the melanoma cell lines
LOX-IMVI, MALME-3M, and M14, the ovarian line OVCAR-3, the renal cancer
lines 786-0, ACHN, CAKI-1, and TK10, the prostate cancer PC3, and the
breast cancer line MDA-MB 231, whereas XIAP protein levels were above
the mean within these same tumor cell lines.
Correlation of IAP Protein Levels with Chemosensitivity Data from
the NCI 60 Cell Screening Panel.
XIAP and cIAP1 protein levels were correlated with cytotoxicity data
for compounds tested against the NCI 60 cell screening panel. Because
cIAP-2 protein was found in only five cell lines, it was excluded from
statistical analysis. Several nucleoside DNA chain-terminating drugs
were positively correlated with XIAP protein levels, suggesting that
drug sensitivity may be associated with expression of this protein
(Table 1A)
. The most significant
correlation was between XIAP protein levels and in vitro
chemosensitivity to cytarabine, indicating a possible role for XIAP in
conferring sensitivity to this agent in vitro (Pearson
correlation coefficient, 0.44; P (two-tail) < 0.0006).
For cIAP1, the most significant correlation was seen between cIAP1
protein levels and in vitro chemoresistance to carboplatin
(P < 0.002) and cisplatin (P < 0.002;
Table 1B
). Significant associations between higher levels of cIAP1
protein and resistance to several DNA alkylating agents and the
topoisomerase inhibitor VP-16 were also observed (Table 1B)
.5
No significant
correlations with drug cytotoxicity data and IAP-family mRNA levels
were found.
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Comparisons of IAP Expression with Clinical Response to
Chemotherapy in AML.
The observed correlation of higher levels of XIAP protein with greater
sensitivity to nucleoside analogue drugs was paradoxical in terms of
a priori expectations based on gene transfection evidence
that overexpression of XIAP protects tumor cell lines from apoptosis
induced by various anticancer drugs (reviewed in Refs. 30
and 31
).
Because XIAP protein levels showed the greatest correlation with
cytarabine (AraC), we explored the relation of XIAP expression to
in vivo drug responses in a clinical context where
AraC-based therapy is standardly used, i.e., in patients
with AML (32)
. All patients were treated with high-dose
AraC-containing regimen. The relative levels of XIAP protein were
compared with clinical responses to chemotherapy, consisting of
high-dose AraC plus idarubicin, using leukemia cell samples derived
from 78 AML patients. Expression of XIAP protein was detected by
immunoblotting in 76 of 78 samples tested; however, the level of XIAP
was very low (<5% of the control cell line) in 20 cases. The range of
expression of XIAP was heterogeneous across all French-American-British
and cytogenetic categories, except for promyelocytic leukemia where
there was a narrow range of expression (not shown). Bcl-2, Bax,
caspase-2, and caspase-3 expression have been measured previously for
most of these patients (25
, 33
, 34)
. No significant
correlation between expression of these other apoptosis-related
proteins and XIAP protein levels was found (data not shown).
To assess possible threshold effects of XIAP protein on survival while
avoiding searching for optimal cutpoints for expression, results were
rank-ordered and then divided into thirds. Because data derived from
patients with XIAP levels in the top two-thirds were similar (not
shown), they were collapsed into one arm for further analysis and
comparison. Patients with lower XIAP levels had significantly longer
survival (median survival, 133 versus 52.5 weeks;
P = 0.05) and a tendency toward longer median remission
duration (87 versus 52.5 weeks; P = 0.13)
than those with higher levels of XIAP. (Table 2
and Figure 4
). For example, 42% of the patients
with low XIAP expression are alive today, as compared with 23% with
high XIAP expression (P = 0.004; Table 2
). Patients
with low levels of XIAP had only a slightly higher complete remission
rate with induction chemotherapy (73% versus 65%;
P = 0.42) but a lower relapse rate (42%
versus 65%; P = 0.17) compared with
patients with XIAP levels in the top two-thirds (Table 2)
. However,
neither the complete remission rate nor relapse rate data reached
statistical significance. No statistically significant differences were
noted between the XIAP high and low groups with respect to age,
cytogenetics, frequency of an antecedent hematological disorder, or
gender; however, patients with higher XIAP were more likely to have
poor Zubrod performance status (Table 2)
.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Interestingly, IAP mRNA and protein levels were commonly noncongruent, suggesting the likelihood of posttranscriptional regulation of the expression of these antiapoptotic genes, perhaps through translational mechanisms or by differential rates of protein turnover. In this regard, evidence of translational control of XIAP has been reported recently, revealing the presence of an internal ribosome entry site within the XIAP mRNA (35) . This lack of correlation between XIAP, cIAP1, and cIAP2 has important implications with respect to any future attempts to use cDNA arrays or related technologies for assessing IAP-family gene expression in cancers. The finding that cIAP1 protein but not cIAP1 mRNA levels were associated with resistance to several anticancer drugs among the tumor cell lines of the NCI 60 cell screening panel lends additional support to the argument that measurements of protein and not mRNA levels are critical to understanding the role of this family of antiapoptotic genes in cancer.
The variability in IAP protein levels seen here among the NCI’s 60 human tumor cell lines suggests that further correlative studies of IAP expression with clinical outcome and with other biomarkers should be informative with regards to assessing the prognostic significance of these antiapoptotic proteins. Moreover, the lack of correlation of IAPs with other known tumor-related genes assessed previously in the NCI 60 cell panel (e.g., c-Jun, Ras, Fos, p53, and Rb) raises the possibility that IAPs could serve as independent risk factors for some types of malignancies, as suggested recently for Survivin (11 , 36 , 37) .
The paradoxical association of XIAP protein levels with sensitivity rather than resistance to AraC and some other nucleoside analogues among the NCI panel of 60 tumor cell lines remains unexplained. We might speculate that a fortuitous correlation exists between XIAP and levels of other proteins that might sensitize cells to such agents, such as nucleotide kinases and phosphatases. Moreover, the correlation between XIAP levels and sensitivity of cell lines to various drugs in vitro does not take into account the clinical usefulness of this approach, e.g., AraC is not the cytotoxic agent of choice for solid tumors. Given the overwhelming evidence that XIAP is a caspase-inhibiting, antiapoptotic protein (reviewed in Refs. 30 and 31 ), this observation illustrates the difficulty in drawing conclusions about protein function from correlative approaches. In this regard, the NCI 60 tumor cell line panel was assembled originally for the purpose of identifying compounds with potential antitumor activity (38) . In recent years, however, attempts have been made to use bioinformatics and genomics technologies to reveal associations between cytotoxic responses of cancer cell lines to compounds and various biomarkers. Future efforts of this type may ultimately provide a molecular explanation for the paradoxical correlation of XIAP protein with greater sensitivity to nucleoside agents.
Although little attempt has been made thus far to compare the levels of IAPs in tumors with other biomarkers or with clinical outcome, it has been reported that Survivin expression in neuroblastomas correlates with clinically more aggressive, histologically unfavorable disease (37) . Moreover, higher levels of Survivin protein as determined by immunostaining and p53 accumulation (indicative of mutant p53) were positively correlated in a survey of gastric cancers (36) , implying an association of Survivin with more aggressive disease.
Prompted by an unexpected inverse correlation between XIAP protein levels and resistance to AraC in the NCI 60 cell screening panel, we compared the expression of this IAP-family member in AML blasts derived from newly diagnosed, untreated patients, making correlations with clinical outcome. Patients with low levels of XIAP (lowest third) enjoyed a significantly longer survival and tended to have longer median remission durations. These data suggest that XIAP may have prognostic potential in AML, a finding that should be evaluated in additional studies involving larger numbers of AML patients and extended to other types of cancer. Moreover, these in vivo data are fitting with expectations based on knowledge of the antiapoptotic activity of XIAP in cells.
These results thus warrant further research on both the functions and prognostic relevance of XIAP and other IAP-family genes in cancer and leukemia.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Generously supported by NIH Grants CA-55164-08,
AG 15402, 5P01CA69381-04, and 5RO1CA97329-05 and a grant from IDUN
Pharmaceuticals, Inc. I. T. is the recipient of a postdoctoral
fellowship from the Mildred-Scheel-Stiftung fuer Krebsforschung,
Germany. 
2 Present address: Humboldt-Universität,
Charité, Medizinische Klinik mit Schwerpunkt Hämatologie,
Onkologie und Tumorimmunologie, Lindenberger Weg 80, D-13125 Berlin,
Germany.
3 To whom requests for reprints should be
addressed, at The Burnham Institute, 10901 North Torrey Pines Road, La
Jolla, CA 92037. Phone: (858) 646-3140, Fax: (858) 646-3194; E-mail: jreed{at}burnham-inst.org
4 The abbreviations used are: IAP, inhibitor of
apoptosis protein; BIR, Baculovirus IAP repeat; NCI, National Cancer
Institute; AML, acute myelogenous leukemia; AraC, cytarabine; RPA,
RNase Protection Assay; GAPDH, glyceraldehyde-3-phosphate
dehydrogenase; CNS, central nervous system; VP-16, etoposide.
5 A complete list of the tested cytostatic drugs
is available through the Internet at
http://epnws1.ncicrf.gov:2345/dis3d/dtp.html.
6 A complete list of the gene targets is available
through the Internet at
http://epnws1.ncicrf.gov:2345/dis3d/dtp.html.
Received 4/15/99; revised 12/28/99; accepted 2/ 8/00.
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