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Tumor Biology |
Departments of Surgery [P. A. C., J. P. N.] and Pathology [A. R. D., Y. K., C. S. F.], The University of Liverpool, and Department of Urology, The Royal Liverpool University Hospital [P. A. C., K. F. P., A. D. D., A. W., M. F.], Liverpool, L69 3GA, United Kingdom
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSWestern Blotting Cell LinesDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSWestern Blotting Cell LinesDISCUSSIONREFERENCES |
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hsp27 is constitutively expressed at low levels in the cytosol of most human cells (13) . After induction, the protein becomes phosphorylated while simultaneously translocated from the cytoplasm to within or around the nucleus (14, 15, 16) . Phosphorylation is a key regulator of hsp27 function occurring at serine residues 78 and 82 (17) through interaction with a specific kinase, but it may be activated by several different signal transduction mechanisms. The presence of the protein contributes to cell survival after diverse stress insults (14 , 16 , 18) . In murine L929 (19) and in human HT-29 and CaCo2 colorectal cancer cell lines (20) , hsp27 inhibits apoptosis induced by a variety of different stimuli. It has been proposed that hsp27 modulates reactive oxygen species via a glutathione-dependent pathway (21) , thereby protecting intracellular proteins and explaining, in part, the protective effect of hsp27 against chemotherapeutic agents (22 , 23) .
hsp60 is abundant in most mammalian cells under normal conditions (24) , where its major functions are protein chaperoning and protein folding (25) . Both processes are coregulated by hsp10 (26) . Whereas aberrant expression of hsp60 has been associated with autoimmune disease, hsp60 has a role together with hsp70 in antigen presentation in malignant diseases (27) , with enhanced hsp60 expression reported in breast carcinoma (28) and myeloid leukemia (29) .
hsp70 regulates a wide range of protein-associated activities
(13
, 30, 31, 32, 33)
. Expression of hsp70 is enhanced after
transformation by oncogenes (34
, 35)
. Elevated levels of
hsp70 protect cells from apoptotic death induced by TNF-
and TNF-ß
(36)
. hsp70 interacts with p53 to stabilize mutant but not
the wild-type protein (37)
. Conversely, wild-type (but not
mutant) p53 down-regulates hsp70 expression (38)
.
Our recent studies demonstrated that expression of other homeostatic regulator proteins, including PKC isoenzymes (39) , Ca2+-binding proteins (40) , and ion channels (41 , 42) , are differentially modulated in prostate cancers. When enhanced, these proteins promote the metastatic phenotype, and their expression predicts poor clinical outcome (39) . Because some members of the PKC and hsp families are integral components of the same intracellular information cascades, together promoting cell migration, inhibiting proliferation, and down-regulating apoptosis, it was predicted that expression of some hsps would also contribute to the behavioral phenotype of individual prostate cancers. Therefore, this study was undertaken to test the hypothesis that hsps are differentially expressed during induction and progression of prostatic neoplasia and that particular hsps, together with other homeostatic regulatory proteins, determine the clinical outcome of individual prostate cancers. Identification of such proteins at the time of diagnosis could provide new prognostic information with respect to the behavioral or responsive phenotype of prostate cancers, thus influencing appropriate clinical management for individual patients. Depending on their critical roles in maintaining cellular integrity and function, this spectrum of homeostatic proteins may also become a target for novel forms of tumor-specific therapeutic intervention (43) .
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSWestern Blotting Cell LinesDISCUSSIONREFERENCES |
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Control Tissues.
Prostates removed from men (n = 10; mean age,
52.4 years) undergoing primary cystoprostatectomy for invasive
transitional cell carcinoma of the urinary bladder were used to control
the immunohistochemical findings on the radical prostatectomy tissues.
All of these patients were asymptomatic for lower urinary tract
symptoms. Prostate samples removed at TURP (n = 50; mean age, 70.2 years; range, 54–84 years) were used to
control the findings in prostatic carcinoma specimens obtained at TURP
and comprising 10 incidentally identified carcinomas and 85 advanced
carcinomas, as detailed below. All control specimens were reviewed
microscopically to confirm the absence of incidental PIN and carcinoma
of either prostatic or bladder origin.
Prostate Carcinoma Tissue.
Three groups of tissues were examined: (a) radical
prostatectomy specimens obtained from 25 consecutive and otherwise
unselected patients with organ-confined disease
(pT1–2N0M0);
(b) specimens from 10 patients with incidentally diagnosed
early invasive prostate cancer
(pT1N0M0)
at TURP for lower urinary tract symptoms; and (c)
transurethral resection specimens from 85 patients with advanced
prostate cancer
(pT33–4NxM0–1)
who had undergone BSCO at least 3 months previously. Patients were
clinically staged by digital rectal examination, serum PSA, bone scan,
and chest X-ray. Patients undergoing radical prostatectomy were also
assessed by transrectal ultrasound scanning and with abdominal computed
tomography scan or, after 1994, transrectal magnetic resonance imaging.
Patient demographic details and tumor characteristics are detailed in
Table 1
.
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Of the radical prostatectomy group (n = 25), at the time of last follow-up, one patient had died of recurrent prostatic carcinoma at day 1123 after surgery, and two patients had clinical evidence of recurrent tumor recorded at 578 and 1665 days after surgery. A fourth patient recorded an elevated serum PSA (7.2 µg/liter) and was considered to have chemical evidence of recurrence (PSA began to rise 1004 days after surgery). Three patients died of unrelated noncancer causes with no evidence of recurrent carcinoma and were deemed to be disease free.
Four patients with incidentally diagnosed prostate cancer (n = 10) died of unrelated conditions, whereas six remain alive and well with no evidence of disease progression. None of these patients required hormonal manipulation. Of the 85 patients with advanced prostate cancer 44 (51.7%) died of prostate cancer, 2 (2.4%) patients had evidence of either chemical or clinical progression, 16 (18.8%) died of other causes without evidence of disease progression, and 23 (27.1%) patients remain alive and show no evidence of disease progression.
Gleason grading of all prostatic carcinomas included in this study was performed by two pathologists according to conventional criteria (44) .
Antibodies and Antisera.
Murine monoclonal antibodies to hsp27 and hsp70 were purchased
from Novacastra (Novocastra Laboratories Ltd., Newcastle upon Tyne,
United Kingdom). The antibody against hsp60 was purchased from
Stress Gen Biotechnologies Corp. (York, United Kingdom). Biotinylated
antimouse immunoglobulin raised in sheep was purchased from Amersham
Life Science (Little Chalfont, United Kingdom). Microwave antigen
retrieval was performed at 850 W for 15 min in 10 mM EDTA
solution (pH 7.0), and samples were then allowed to cool to room
temperature over a 15-min period. All antibodies were diluted in TBS
containing 5% (w/v) BSA to the concentration shown in Table 2
.
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Analysis of hsp Expression.
Specimens were considered positive only when at least 5% of the
contained epithelial cells (either normal or malignant) unequivocally
expressed hsp staining. The 5% cutoff was chosen because it conforms
to the international European Organization for Research and Treatment
of Cancer-Gynaecological Cancer Cooperative Group
recommendations (45)
. Furthermore, this cutoff was used as
the criterion to distinguish positive and negative immunohistochemical
staining in our previous studies of prostate cancer including MHC
expression (46)
and PKC isoenzyme expression by this
identical group of prostatic neoplasms (39)
, thus ensuring
consistency of criteria between studies. For each tissue section,
staining was assessed as negative, weakly positive or only focally
positive (low-level expression), or strongly positive (high-level
expression) and scored as 0, 1, or 2, respectively. For positive
sections, the assessments made were: (a) cellular
distribution of each hsp in benign and malignant human prostatic
epithelium; and (b) the relationship between expression of
hsp and tumor grade.
Cell Lines.
Expression of hsps by human transformed benign prostate cell line PNT2
(43)
, androgen-sensitive prostate cancer cell line LNCaP
(44)
, and androgen-resistant cell lines DU145
(45)
and PC3 (46)
was analyzed. Cells were
grown as monolayers in RPMI 1640 (Life Technologies, Inc.) supplemented
with 10% FCS (Life Technologies, Inc.), 1 mM glutamine,
100 IU/ml penicillin G, and 100 IU/ml streptomycin in an atmosphere of
5% CO2 in air at 100% humidity and 37°C.
Media were changed on alternate days.
Gel Electrophoresis and Immunoblotting.
Whole cell lysates were prepared in a buffer comprising 50
mM Tris (pH 7.5) containing 1 mM EGTA, 5
mM EDTA, 1% Triton X-100, 140 mM NaCl, 10%
(v/v) glycerol, 25 mM NaF, 1 mM
MgCl2, 10 µg/ml pepstatin, 1 µg/ml leupeptin,
80 µg/ml phenylmethylsulfonyl fluoride, 10 µg/ml aprotinin, to
which was added an equal volume of reducing sample buffer comprising 75
mM Tris (pH 6.8) containing 1% (v/v) ß-mercaptoethanol,
20% (w/v) sucrose, 2% SDS, and 0.001% (w/v) bromphenol blue. The
sample was sonicated for 15 s and centrifuged at 13,500 rpm for 15
min to remove debris. Protein concentration in the supernatant was
measured using the Bradford Assay (Bio-Rad Laboratories Ltd., Hemel
Hemstead, United Kingdom). Protein aliquots (100 µg) were separated
by 10% (w/v) SDS-PAGE. To verify that equal amounts of proteins were
loaded onto the stacking gel, actin expression was estimated in each
lane by Western blotting using antiactin monoclonal antibody (Dako;
Table 2
) After separation, proteins were transferred to a
nitrocellulose membrane by electroblotting. Thereafter, blots were
blocked by immersion for 1 h at room temperature in 10
mM Tris buffer (pH 7.5) containing 5% (w/v) skimmed milk,
100 mM NaCl, and 0.1% (v/v) Tween 20 (Tris-Tween) and
probed with the identical monoclonal antibodies used for
immunohistochemistry at the concentrations shown in Table 2
. After
three 15-min washes in Tris-Tween, blots were incubated with
peroxidase-conjugated secondary antibodies. The enhanced
chemiluminescence Western blotting analysis system (Amersham Life
Science) was subsequently used for protein detection. Blots were
repeated twice to confirm data.
Statistical Analyses.
Statistical values of significance were determined using the
2
test to compare nominal data. Correlations
were assessed using the Kruskal-Wallis test for nonparametric data.
Survival advantage was calculated by Kaplan-Meier analysis. Cox
proportional hazard regression analysis was used to assess the
relationship of each of the clinicopathological factors with
disease-free survival in the advanced prostate cancers previously
treated with BSCO. Age, hsp27 staining, preoperative PSA,
Gleason grade, and clinical stage were included as covariates for the
first analysis. Stepwise procedure selected pathological stage, Gleason
grade, and hsp27 as significant prognostic factors (race was not
included because all patients were Caucasians and indigenous to
Liverpool-Merseyside). Statistical significance was set at
P < 0.05. All calculations were performed
using Stat View statistical software.
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RESULTS |
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. Staining
was characteristically cytoplasmic and finely granular. Basal cells as
well as luminal epithelial cells were stained. Expression of hsp27 in
the 50 BPH tissues occurred with a frequency similar to that seen in
the 10 normal controls, so that no qualitative or quantitative
differences in staining were identified when these tissues were
compared. With respect to early malignancy
(pT1–2), as defined in the 25 radical
prostatectomy specimens, there was a highly significant
(P < 0.0001) decrease in expression of
hsp27, such that the neoplastic components in 21 of the 25 specimens
(84%) did not express this protein. However, expression of hsp27 by
adjacent nonneoplastic epithelial components was indistinguishable from
that found in the control normal and BPH tissues. A similar pattern was
seen in the 10 incidental prostate cancers diagnosed on TURP. Whenever
PIN was identified according to morphological criteria, staining was
heterogeneous with respect to hsp27 expression (Fig. 1a)
. Of the 85 invasive
prostate cancers
(pT3–4NxM0–1),
38 (45%) were positive (P < 0.0001) for
hsp27, with hsp27 protein expressed as fine granules distributed
throughout the cytoplasm of the malignant cells in different regions of
their invasive components (Fig. 1b)
. A strong correlation
was demonstrated between hsp27 expression by each of the 85 invasive
carcinomas and its corresponding Gleason grade (P < 0.04; Fig. 2
). However, of
greater importance was the more significant correlation between hsp27
expression and tumor behavior (P < 0.0001)
confirmed on univariate analysis (Fig. 3)
. This relationship became an even more
powerful predictor of poor clinical outcome on Cox regression analysis
(P = 0.014; Table 4
).
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. Although the distribution of this
protein was also cytoplasmic, the appearance of the stained protein was
coarsely granular, in contrast to that seen for hsp27 and hsp70. An
appreciable amount of epithelium in all BPH tissues expressed hsp60.
Whereas this expression was heterogeneous, varying in intensity
according to location, its presence was not simply related to some
obvious factor, such as adjacent inflammation, but appeared to be
endogenous to the particular region of epithelium. Similarly, the
in situ neoplastic and invasive malignant components in all
of the radical prostatectomy and TURP specimens variably expressed
hsp60 protein. Characteristically, the appearance of the coarse
granular cytoplasmic deposits of protein in the cancer cells appeared
more numerous and intense than those in the nonneoplastic component of
the corresponding specimen (Fig. 1c)
. In regions of
high-grade PIN, expression of hsp60 was elevated when compared with BPH
and with normal control tissues. In 24 of 25 (96%) radical
prostatectomies and 83 of 95 (87%) morphologically advanced invasive
prostate cancers, hsp60 expression was strong when compared with that
of nonneoplastic tissues (P < 0.0001). With
respect to semiquantitative assessment of the level of hsp60 expression
and Gleason grade, no association was apparent in either the early or
the advanced cancers.
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Characteristically, staining was uniformly cytoplasmic and varied from
diffusely nongranular to finely granular. In 6 of the 50 (12%) BPH
tissues, no staining of the epithelium was identified. Neither the
in situ neoplasia nor the invasive malignant component in 4
of 25 (16%) radical prostatectomies and 30 of 95 (32%) advanced
invasive carcinomas expressed hsp70. This finding was of only moderate
statistical significance (P < 0.005) with
respect to the control normal tissues. Immunohistochemical expression
of this protein by invasive prostate cancer cells (Fig. 1d)
was generally less intense, although of the same character
(i.e., uniform and finely granular) as that in the
nonmalignant epithelium. No association was found between intensity of
staining and Gleason grade in either the early or the advanced cancers,
so that some Gleason grade 5 carcinomas expressed this protein very
strongly (Fig. 1e)
.
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Western Blotting Cell Lines |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSWestern Blotting Cell LinesDISCUSSIONREFERENCES |
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. hsp27 was
not detectable in transformed cell line PNT2 but was weakly expressed
in LNCaP. Expression of hsp27 was stronger in androgen-independent cell
lines DU145 and PC3 (Fig. 4)
, a finding
that correlated with data from tissue specimens in which enhanced
expression occurred in less differentiated tumors. The finding that
expression of hsp60 was barely detectable in PNT2 cells but appreciably
enhanced in all three malignant cell lines, particularly LNCaP, is
consistent with data from tissue specimens in which increased
expression occurred in invasive cancers but with no identifiable
difference in relative expression between stage or grade of individual
cancers. Expression of hsp70 was found only in the LNCaP cell line.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSWestern Blotting Cell LinesDISCUSSIONREFERENCES |
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In the normal prostate, hsp27 was expressed in both luminal and basal
epithelial cells, particularly the latter. However, it was not
identified in early dysplastic lesions of intact tissues, including
PIN, or in transformed cell line PNT2. Whereas failure to express hsp27
in the PNT2 cell line might be related to transformation, its
expression was much stronger in androgen-independent cell lines (Fig. 4)
, which correlates with findings in the intact tissue specimens,
where enhanced expression occurred in less differentiated tumors. The
observation that early dysplastic lesions, including PIN, invariably
failed to express hsp27 is a finding now being evaluated as an
objective assessor of dysplastic transformation. In a range of human
tissues, hsp27 is a marker of functional estrogen receptors such that
in both breast and endometrial carcinoma, hsp27 overexpression has been
correlated with differentiation (47)
. In prostate cancer
cell lines, estradiol-induced growth inhibition may be mediated through
hsp27 by transforming growth factor ß1 (48)
.
Expression of hsp60 was barely detectable in PNT2 cells but appreciably enhanced in all three malignant cell lines, and consistent with our findings in tissue specimens where increased expression occurred in the cancers, but was unrelated to the stage or grade of each individual cancer. In limited studies of normal tissues, expression levels of hsp60 correlate directly with the requirement to regenerate mitochondria after cell proliferation or after high mitochondrial activity.
Expression of hsp70 was not found in the intact tissues and was found
only in the LNCaP cell line. Its presence protects cells from diverse
types of stress including heat, TNF-, and ceramide but not ionizing
radiation (49)
. It is suggested that this group of hsps
should be classified, together with Bcl-2, as inhibitors of apoptosis.
Activation of the latent DNA binding function of human p53 protein by
hsp70 represents a unique reaction in which a hsp interacts with a
native protein to affect its function (50)
.
Induction of latent hsp70 results in its binding to a divergent group
of proteins including members of the PKC family (51)
, the
expression of which has been shown to correlate with the behavioral
phenotype of prostate cancer (39)
.
Despite the expected variability in expression of individual hsps of differing intracellular homeostatic functions, the current data demonstrate that hsp27 expression is highly correlated with the clinical outcome of individual prostate cancers. However, our observations are at variance with an early report by Storm et al. (52) , who found no expression of hsp27 in either normal or neoplastic prostatic epithelium. This is surprising because hsp27 is ubiquitous in normal tissues, and its enhanced expression had already been correlated with poor prognosis in human breast cancer (53 , 54) . In contrast, and with findings similar to those we now report, Thomas et al. (55) confirmed strong immunohistochemical staining for hsp27 in benign prostatic epithelium, with heterogeneous expression being described in both PIN and invasive prostate cancer. In the latter, reduction in staining reflected increasing Gleason score and invasiveness. A smaller but more detailed study of seven cases of prostate cancer found that whereas differential expression of hsp27 occurred in nonneoplastic basal and luminal epithelial cells, this protein was generally absent in regions of established malignancy (56) . Nevertheless, after thermal stress of prostatic carcinoma tissues in vivo, hsp27 expression could be up-regulated in a manner similar to that we described recently in human normal epidermis (57) .
Our observations strongly support previous studies by Thor et al. (58) , Chamness et al. (53) , and Tandon et al. (54) , who reported that hsp27 overexpression was correlated with reduced overall survival of patients with breast cancer. Those findings were extended by Conroy et al. (59) , who showed that production of anti-hsp27 autoantibodies also correlated with improved survival in breast cancer patients. The current study confirms and extends the novel and innovative work of Bubendorf et al. (60) , who showed, using DNA microassay technology, that the gene encoding hsp27 was among the most consistently overexpressed genes in hormone-refractory prostate cancer xenografts when compared with the parental, hormone-sensitive strain of the same cancer. To validate their findings in intact prostate cancers, immunohistochemical analysis of human tissue microassays confirmed overexpression of hsp27 in 31% of the hormone-refractory tumors, a finding in agreement with our observation of increased expression in the more malignant tumors. Surprisingly, and in contrast to our data and the findings of previous investigators (55 , 56) , none of the benign prostatic tissues expressed this protein. This is an important discrepancy that may be explained, in part, by possible differences in epitope specificity of the various monoclonal antibodies used in the different studies. Apparent disparity in the immunohistochemical observations is unlikely to be due to errors in tissue sampling for the microassay technology because this potential error has already been identified and fully addressed by the authors, with high concordance demonstrated in their previous work (61 , 62) . In our current study, we were able to validate the identity of the protein identified immunohistochemically by Western blotting the cell lines using the same monoclonal antibody used for the immunohistochemistry.
Our previous analysis of PKC isoenzyme expression by this identical group of early prostate cancers revealed a correlation between strong PKC-ß expression, aggressive behavioral phenotype, and poor clinical outcome (39) , which is similar to that now demonstrated for hsp27. This finding is not surprising because hsp27 and PKC-ß are not only regulators of metabolic homeostasis but are also components of the same intracellular information cascades. Activation of PKC results in phosphorylation of hsp27, which, in turn, determines expression or activity of androgen and/or estrogen receptors. Because nonneoplastic control epithelia normally express hsp27, it was surprising to find that strong expression of hsp27 or PKC-ß by invasive prostate cancers correlated with poor clinical prognosis. One hypothesis to account for this observation is that the PKC-ß-hsp27 pathway becomes promiscuous in malignant cells, thus modulating one or more proteins that are differently expressed between nonneoplastic and malignant epithelia. Whereas the PKC-ß-hsp27 axis is both powerful and important to intracellular homeostasis, it is unlikely to be the sole control of the metastatic malignant phenotype of prostate cancer cells. To be successfully metastatic, prostate cancer cells abrogate cell surface expression of MHC class I and class II molecules (46 , 63) as well as p170, the volume-regulated Cl- ion channel (41) . Conversely, neoexpression of voltage-gated Na+ and K+ channels and enhanced expression of Ca2+-binding protein p9Ka (40) appear to be prerequisites for development of the malignant phenotype (43) . To date, no functional relationship has been reported between modulation of these proteins and expression of either PKC-ß or hsp27 in prostate cancer.
In summary, this examination of a large number of well-characterized human prostate tissues (60 benign and 120 malignant tissues) has confirmed that enhanced or maintained expression of hsp27 protein is an independent and accurate predictor of poor clinical outcome for individual prostate cancers. Two corollaries arise from these observations: (a) hsp27 and PKC-ß should be further investigated as powerful objective discriminants to predict likely clinical behavior and possibly to determine appropriate therapeutic strategies for individual patients with prostate cancer; and (b) hsp27 (together with or independently of PKC-ß) may be useful a target for developing novel therapeutic approaches aimed at controlling the aggressive malignant phenotype of early but locally invasive prostate cancers expressing these proteins.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by grants from the Trust
Research Fund, Research and Development Office, Royal Liverpool and
Broadgreen Hospitals NHS Trust, The Prostate Cancer Charity, and the
Merseyside Prostate Cancer Trust (to C. S. F.). 
2 P. A. C. is the current holder of the Insole
Award and Tomkinson Award, British Medical Association, United Kingdom.
3 To whom requests for reprints should be
addressed, at Department of Cellular and Molecular Pathology,
University of Liverpool, Duncan Building, Daulby Street, Liverpool, L69
3GA, United Kingdom.
4 The abbreviations used are: hsp, heat shock
protein; PIN, prostatic intraepithelial neoplasia; PSA,
prostate-specific antigen; BPH, benign prostatic hyperplasia; TURP,
transurethral resection of prostate; TNF, tumor necrosis factor; PKC,
protein kinase C; BSCO, bilateral subcapsular orchidectomy; TBS,
Tris-buffered saline.
Received 9/17/99. Accepted 10/16/00.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSWestern Blotting Cell LinesDISCUSSIONREFERENCES |
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ß-crystallin expression-mediated increase in gluthathione is essential for the protective activity of these proteins agains TNF--induced cell death. EMBO J., 15: 2695-2706, 1996.[Medline]
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P. Rocchi, A. So, S. Kojima, M. Signaevsky, E. Beraldi, L. Fazli, A. Hurtado-coll, K. Yamanaka, and M. Gleave Heat Shock Protein 27 Increases after Androgen Ablation and Plays a Cytoprotective Role in Hormone-Refractory Prostate Cancer Cancer Res., September 15, 2004; 64(18): 6595 - 6602. [Abstract] [Full Text] [PDF]
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Y. Wang, J. R. Theriault, H. He, J. Gong, and S. K. Calderwood Expression of a Dominant Negative Heat Shock Factor-1 Construct Inhibits Aneuploidy in Prostate Carcinoma Cells* J. Biol. Chem., July 30, 2004; 279(31): 32651 - 32659. [Abstract] [Full Text] [PDF]
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S. C.G. Hollestelle, M. R. de Vries, J. K. van Keulen, A. H. Schoneveld, A. Vink, C. F. Strijder, B. J. van Middelaar, G. Pasterkamp, P. H.A. Quax, and D. P.V. de Kleijn Toll-Like Receptor 4 Is Involved in Outward Arterial Remodeling Circulation, January 27, 2004; 109(3): 393 - 398. [Abstract] [Full Text] [PDF]
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 D. Chauhan, G. Li, T. Hideshima, K. Podar, C. Mitsiades, N. Mitsiades, L. Catley, Y. T. Tai, T. Hayashi, R. Shringarpure, et al. Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance Blood, November 1, 2003; 102(9): 3379 - 3386. [Abstract] [Full Text] [PDF]
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 L. Shatkina, S. Mink, H. Rogatsch, H. Klocker, G. Langer, A. Nestl, and A. C. B. Cato The Cochaperone Bag-1L Enhances Androgen Receptor Action via Interaction with the NH2-Terminal Region of the Receptor Mol. Cell. Biol., October 15, 2003; 23(20): 7189 - 7197. [Abstract] [Full Text] [PDF]
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 D. de Kleijn and G. Pasterkamp Toll-like receptors in cardiovascular diseases Cardiovasc Res, October 15, 2003; 60(1): 58 - 67. [Abstract] [Full Text] [PDF]
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 G. S. Missotten, J. G. J.-d. Korver, D. de Wolff-Rouendaal, J. E. Keunen, R. O. Schlingemann, and M. J. Jager Heat Shock Protein Expression in the Eye and in Uveal Melanoma Invest. Ophthalmol. Vis. Sci., July 1, 2003; 44(7): 3059 - 3065. [Abstract] [Full Text] [PDF]
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H. Sakamoto, T. Mashima, K. Yamamoto, and T. Tsuruo Modulation of Heat-shock Protein 27 (Hsp27) Anti-apoptotic Activity by Methylglyoxal Modification J. Biol. Chem., November 22, 2002; 277(48): 45770 - 45775. [Abstract] [Full Text] [PDF]
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