Amplification and co-regulators of androgen receptor gene in prostate cancer
Prostate cancer isthe second most common malignancy among males after lung cancer. The growth of prostate cancer cells depends on the presence of androgens, a group ofsteroid hormones that include testosterone and its more active metabolite dihydrotestosterone. Most prostate cancers are androgen-d...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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| Цитувати: | Amplification and co-regulators of androgen receptor gene in prostate cancer / Ch. Golias, I. Iliadis, D. Peschos, K. Charalabopoulos // Experimental Oncology. — 2009. — Т. 31, № 1. — С. 3-8. — Бібліогр.: 46 назв. — англ. |
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Golias, Ch. Iliadis, I. Peschos, D. Charalabopoulos, K. 2018-06-14T11:37:00Z 2018-06-14T11:37:00Z 2009 Amplification and co-regulators of androgen receptor gene in prostate cancer / Ch. Golias, I. Iliadis, D. Peschos, K. Charalabopoulos // Experimental Oncology. — 2009. — Т. 31, № 1. — С. 3-8. — Бібліогр.: 46 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/134927 Prostate cancer isthe second most common malignancy among males after lung cancer. The growth of prostate cancer cells depends on the presence of androgens, a group ofsteroid hormones that include testosterone and its more active metabolite dihydrotestosterone. Most prostate cancers are androgen-dependent and respond to the antiandrogens or androgen-deprivation therapy. However, the progression to an androgen-independent stage occurs frequently. Possible mechanisms that could be involved in the development of hormone resistant prostate cancer causes including androgen receptor (AR) mutations, AR amplification/over expression, interaction between AR and other growth factors, and enhanced signaling in a ligand-independent manner are discussed. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Reviews Amplification and co-regulators of androgen receptor gene in prostate cancer Article published earlier |
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Amplification and co-regulators of androgen receptor gene in prostate cancer |
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Amplification and co-regulators of androgen receptor gene in prostate cancer Golias, Ch. Iliadis, I. Peschos, D. Charalabopoulos, K. Reviews |
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Amplification and co-regulators of androgen receptor gene in prostate cancer |
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Amplification and co-regulators of androgen receptor gene in prostate cancer |
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Amplification and co-regulators of androgen receptor gene in prostate cancer |
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Amplification and co-regulators of androgen receptor gene in prostate cancer |
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amplification and co-regulators of androgen receptor gene in prostate cancer |
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Golias, Ch. Iliadis, I. Peschos, D. Charalabopoulos, K. |
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Golias, Ch. Iliadis, I. Peschos, D. Charalabopoulos, K. |
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Reviews |
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Reviews |
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2009 |
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English |
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Experimental Oncology |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Article |
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Prostate cancer isthe second most common malignancy among males after lung cancer. The growth of prostate cancer cells depends
on the presence of androgens, a group ofsteroid hormones that include testosterone and its more active metabolite dihydrotestosterone.
Most prostate cancers are androgen-dependent and respond to the antiandrogens or androgen-deprivation therapy. However,
the progression to an androgen-independent stage occurs frequently. Possible mechanisms that could be involved in the development
of hormone resistant prostate cancer causes including androgen receptor (AR) mutations, AR amplification/over expression,
interaction between AR and other growth factors, and enhanced signaling in a ligand-independent manner are discussed.
|
| issn |
1812-9269 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/134927 |
| citation_txt |
Amplification and co-regulators of androgen receptor gene in prostate cancer / Ch. Golias, I. Iliadis, D. Peschos, K. Charalabopoulos // Experimental Oncology. — 2009. — Т. 31, № 1. — С. 3-8. — Бібліогр.: 46 назв. — англ. |
| work_keys_str_mv |
AT goliasch amplificationandcoregulatorsofandrogenreceptorgeneinprostatecancer AT iliadisi amplificationandcoregulatorsofandrogenreceptorgeneinprostatecancer AT peschosd amplificationandcoregulatorsofandrogenreceptorgeneinprostatecancer AT charalabopoulosk amplificationandcoregulatorsofandrogenreceptorgeneinprostatecancer |
| first_indexed |
2025-11-25T20:44:26Z |
| last_indexed |
2025-11-25T20:44:26Z |
| _version_ |
1850530985184067584 |
| fulltext |
Experimental Oncology 31, 3–8, 2009 (March) 3
ANDROGEN RECEPTOR AMPLIFICATION
The significance of androgens in the development
of prostate cancer has been known for more than half
century. During the last decade, a lot of efforts has
been made to study the significance of the specific
nuclear receptor of the hormone, androgen recep-
tor (AR). It has been suggested that polymorphisms,
especially the length of CAG repeat in exon 1 of the
gene, are associated with the risk of prostate cancer.
However, not all studies have confirmed the associa-
tion. Most surprisingly, it has now become clear that
prostate carcinomas emerging during the androgen
withdrawal therapy (i. e. hormone-refractory tumors)
are capable of reactivating the AR-mediated signaling
despite of the low levels of androgens. In addition, it has
been shown that AR gene itself is genetically targeted.
Androgen receptor gene amplification (ARGA) has
been suggested as one of the molecular mechanisms
responsible for the development of hormone refractory
prostate cancer. Progression of prostate cancer during
endocrine therapy is a major clinical problem, the mo-
lecular mechanisms of which remain poorly understood.
Amplification of the AR gene was recently described
in recurrent prostate carcinomas from patients who had
failed androgen deprivation therapy [1, 2]. According
to several studies, the frequency of ARGA is stemmed
to be around 30%. On the other hand, insignificant dif-
ferences were found between AR expression in tumors
with and without gene amplification and not all prostate
tumors with ARGA showed increased levels of the
AR protein. These data suggest that other mechanisms
apart from AR amplification are involved in the progres-
sion of prostate cancer. An association between ARGA
and response to therapy has been demonstrated.
In patients who assumed combined androgen blockade
after initial androgen deprivation, a major response
was observed in those with ARGA than in those without
ARGA [2, 3]. In the same study decreased PSA levels
were found in patients with ARGA compared to patients
without it [1, 2]. In contrast, in the bibliography we find
evidence that between PSA expression and ARGA any
correlation might exist. To establish the link between
prostate specific antigen PSA and gene amplification
further investigations are required. During neoplastic
progression, other gene amplification such as p53, myc,
CCND1 or ErbB2 may occur. A recent study provides
evidence of an increasing p53 expression during pro-
gression from an androgen dependent to an androgen
independent prostate cancer, and positive p53+ tumors
were found more frequently in patients with ARGA than
in patients without it. Furthermore, amplification of myc
and ARGA genes was detected in 11% and 22% cases,
respectively in metastases from patients with hormone-
refractory prostate cancer, in comparison to locally
recurrent tumors (4–23%). In summary, neoplastic
progression depends on the accumulation of multiple
genetic alterations some of which may occur at early
stages and others — at late ones. Each molecular event
can influence cell-cycle and apoptosis, and may play
a role as prognostic factor in prostate cancer [4–6].
CO-REGULATORS
There is an evidence that the AR transcriptional
activity is influenced by several co-regulators. These
molecules can either up-regulate (co-activators)
or down-regulate (co-repressors) the AR transcrip-
tional status, usually in a ligand-dependent manner
and generally without binding to DNA. Some of them
such as cyclic AMP binding protein (CBP)/p300 and
steroid receptor coactivator-1 (SRC-1) can induce
DNA modification recruiting the CBP/p300-associated
factor, which possesses histone acetyltransferase
(HAT) activity. Furthermore, the finding that hydroxy-
flutamide can increase AR activity when CBP is over
AMPLIFICATION AND CO-REGULATORS OF ANDROGEN
RECEPTOR GENE IN PROSTATE CANCER
Ch. Golias1, I. Iliadis1, D. Peschos2, K. Charalabopoulos1, *
1Department of Physiology, Clinical Unit, Medical Faculty, University of Ioannina, Ioannina 45100, Greece
2Department of Forensic Sciences, Medical Faculty, University of Ioannina,Ioannina 45100, Greece
Prostate cancer is the second most common malignancy among males after lung cancer. The growth of prostate cancer cells depends
on the presence of androgens, a group of steroid hormones that include testosterone and its more active metabolite dihydrotestoste
rone. Most prostate cancers are androgendependent and respond to the antiandrogens or androgendeprivation therapy. However,
the progression to an androgenindependent stage occurs frequently. Possible mechanisms that could be involved in the develop
ment of hormone resistant prostate cancer causes including androgen receptor (AR) mutations, AR amplification/over expression,
interaction between AR and other growth factors, and enhanced signaling in a ligandindependent manner are discussed.
Key Words: prostate cancer, androgen receptors, coregulators.
Received: December 12, 2008.
*Correspondence: Fax: 003 26510 97850
E-mail: kcharala@cc.uoi.gr
Abbreviations used: AR — androgen receptor; ARA — androgen re-
ceptor — associated coregulator; ARGA — androgen receptor gene
amplification; CBP- cyclic AMP binding protein; DHT — dihydrotes-
tosterone; FHL2 — four and a half LIM domains 2; GF — growth
factors; HAT — histone acetyltransferase; MAPK — mitogen acti-
vated protein kinase; PHD — plant homodomain; PSA — prostate
specific antigen; SRC-1 — steroid receptor coactivator-1.
Exp Oncol 2009
31, 1, 3–8
REvIEwS
4 Experimental Oncology 31, 3–8, 2009 (March)
expressed confirms the hypothesis that co-regulators
can interfere with the effects of antiandrogens by al-
tering the AR ligand specificity and thus contributing
to the progression of prostate cancer [7, 8]. Various
studies reported different results regarding the co-
regulators expression in prostate cancer. Scientists
by using RT-PCR method found that ARA54, ARA70,
and SRC-1 were expressed in both tumor and normal
cultured prostate cells. ARA55 was not expressed
in androgen-independent LNCaP and DU145 prostate
cancer cell lines, while its very low levels were detected
in PNT2 cell line [9, 10]. Additionally, other studies have
demonstrated, by the method of in situ hydritization,
higher levels of the co-regulator Ran/ARA24 in pros-
tate tumor specimens. In contrast, other scientists
did not find overexpression of ARA24 using RT-PCR
in prostate cancer xenografts and cell lines. Perhaps
this discrepancy could be explained by the fact that
in situ hydritization is a poor quantitative method.
Also, SRC-1 expression appeared to be reduced. This
finding correspondes to the results of another group
of scientists who demonstrated lower SRC-1 expres-
sion in hormone refractory LNCaP cells in comparison
to hormone dependent LNCaP cells [9–11]. In contrast,
another study detected elevated levels of SRC-1 pro-
tein in androgen independent prostate cancer [10, 12].
Differences in cell cultures conditions, cell density,
methods of analysis and various types of cell lines may
explain these divergent results. However the weight
of evidence sustains the expression and the biological
role of co-regulators in AR modulation and promotion
to advanced prostate cancer.
ARA54
Ara54 is a protein of 474 aminoacids and molecular
weight of 54kDa that is shown to increase AR tran-
scriptional activity in a DU145 cell line. ARA54 contains
a conserved RING finger motif and a B-box like struc-
ture. It has been reported that the C-terminal region,
without the RING finger motif, may exert inhibitory ef-
fect on AR-mediated transactivation. ARA54 may also
enhance the transcriptional status of LNCaP mutant
AR (ART877a) but not wild type AR or another mutant
AR (Are708k). A mutant ARA54 form (mt-ARA54),
with a point mutation at aminoacid 472 and incapable
to bind to AR, can suppress the positive AR trans-
activation of endogenous or exogenous full-length
f-l ARA54. Furthermore, the inhibition was higher for
exogenous f-l ARA54 in DU145 cells than for endoge-
nous in PC-3 and LNCaP cells, probably because
of the intervention of other coactivators in PC-3 and
NCaP cells. Moreover, mt-ARA54 disrupts the inter-
action between lf-ARA54 and fl-ARA54 molecules
by forming dimers with fl-ARA54, suggesting that
ARA54 may need to form homodimers to increase
AR transcriptional status. These findings underline that
dominant-negative mutant forms of ARA54 or of other
co-regulators, should be considered as potential tar-
gets for prostate cancer therapy [9, 13].
ARA55
ARA55 consists of 444 aminoacids and has a molecu-
lar weight of 55 kDa. There is a sequence homology bet-
ween human ARA55 gene and mouse TGF-β1 inducible
gene hic-5. ARA55 seems to have a role in the stromal
epithelial interaction involved in developing human fetal
prostate. ARA 55 was found to be expressed in stromal
cells with a zonal pattern, primarily in the peripheral zone
surrounding the non canalized acini. Tissue distribution
studies suggest that ARA55 may be differentially ex-
pressed during various stages of prostate cancer. Higher
ARA55 levels were detected in tissue specimens from
androgen-independent prostate cancers than in those
from androgen-dependent prostate cancers [10, 14,
15]. In contrast, using RT-PCR scientists found lower
ARA55 levels in the tissue samples of androgen-indepen-
dent prostate cancers in comparison to untreated pros-
tate cancers or benign prostatic hypertrophy specimens
[16]. On the other hand, higher ARA55 expression levels
in patients with androgen — independent prostate cancer
were associated with shorter recurrence free survival and
overall survival. ARA55 is able to bind to AR in a ligand-
dependent manner and increase its transcriptional status.
The interaction occurs via the C-terminal half of ARA55,
which includes three LIM motifs. Also it has been reported
that ARA55 can induce AR transactivation in response
to antiandrogens like hydroxyflutamide and other non an-
drogenic steroids including 17β-estradiol. In LNCaP cells,
a dominant-negative AR associated protein (dARA55)
co-regulator inhibits the AR transcriptional activity and re-
duces the agonistic action of antiandrogens. dARA55 also
inhibits PSA expression and prostate cancer cell proli-
feration and therefore, should be considered as a gene
therapeutic agent [14–16]. A correlation was found be-
tween ARA55 and proline-rich tyrosine kinase 2 (Pyk2).
Pyk2 is a member of the focal adhesion kinase (FAK)
family and may be linked to the mitogen activated protein
(MAP) kinase and JNK signaling pathways. As it was de-
monstrated in human prostate cancer cell lines, Pyk2 can
directly phosphorylate ARA 55 at tyrosine 43, resulting
in its inactivation. The inactivation may occur either
by impairment of the activity or by sequestration of the
co-activator, and the consequence is the suppression
of the AR transcriptional action. However, the phospho-
rylation site is not found in the AR interaction domain
of ARA55 (aminoacids 251–444), suggesting that other
mechanisms could be involved in the suppression of the
AR transactivation [17, 18].
ARA70
ARA70, found in a DU-145 prostate cancer cell
line, was the first AR co-regulator identified. There
is a growing evidence that this protein may be impli-
cated in the enhancement of the AR transcriptional
activity through a specific ligand binding. It is reported,
that it can also increase the transcriptional activity
of other steroid receptors like the glucocorticoid re-
ceptor (GR), progesterone receptor (PR) and estro-
gen receptor (ER). However, the levels are increased
slightly (up to 2-fold) in comparison to the enhance-
Experimental Oncology 31, 3–8, 2009 (March) 5
ment of AR (up to 10-fold). One study showed that the
consensus FXXLF motif within the ARA 70-N2 domain
(aminoacids 176–401) is important for the interaction
with the AR. The LXXLL motifs, essential for the function
of co-regulators such as the p160 co-regulator, do not
have an important role in ARA70 interaction [19–21].
Whether this molecule is involved in the progres-
sion of prostate cancer is of relevant interest. The
detection of ARA70 in AR-positive LNCaP cells but not
in AR-negative DU 145 cells probably indicates a modifi-
cation of expression and ability to interact with AR during
the progression of prostate cancer from a hormone-
sensitive to a hormone-insensitive state. Recently,
elevated ARA70 expression was found in high grade
prostate cancer tissues as well as in hormone refrac-
tory LNCaP xenografts and prostate cancer cell lines.
Moreover, higher ARA70 protein levels (91.74%) were
detected in prostate cancer specimens than in benign
tissue (64.64%). In addition, one study demonstrated
enhanced ARA70 mRNA levels in a recurrent androgen-
independent CWR22 prostate cancer xenograft, derived
from an androgen-stimulated state after castration.
ARA 70 has been extensively examined as a molecule
that may potentiate AR transcriptional activity not only
in the presence of androgens but also in the pre sence
of antiandrogens and 17β estradiol [20]. Several stu-
dies of HeLa, PC3 and TSU-Pr1 cell lines establish
the induction of AR by 17β estradiol in the presence
of ARA70. However, the results of two different studies
in CV-1 cells regarding ARA70 and 17β estradiol — me-
diated AR transactivation are contradictory. The reason
of these opposing results is not yet known. Prostate
cancer may continue to proliferate in response to an-
tiandrogens (hydroxyflutamide and bicalutamide) and
the role of ARA 70 is critical for this process. In LNCaP
cell line, the addition of a dominant negative AR co-
regulator ARA 70 (aARA70N), lacking AR interaction,
blocks the ARA70-enhanced AR transcriptional activity
by forming a non-functional heteromer with ARA70. The
RNA-interference-mediated silencing of ARA70 gene
confirms this observation [19, 20–23].
ARA267-a
ARA267-a is an AR co-regulator containing the
SET domain with 130 aminoacid motif named from
three originally identified proteins, Su(var)3–9,
Enhancer-of-zeste and Thritorax. It also contains
two LXXLL motifs, three nuclear translocation signal
(NLS) sequences and four plant homodomain (PHD)
finger domains. Recent data show that ARA267-a can
increase the AR transactivation in prostate cancer
cells, probably by binding to DNA and remodeling
of chromatin structure. The SET domain and the PHD
fingers may play important roles in AR-mediated
gene transcription. In addition, it can not be excluded
that the LXXLL motifs, motifs essential for the func-
tion of the co-regulators SRC-1 and TIFII, may also
be important for the ARA267-a function. Finally, ac-
cording to the results of a recent study, an interaction
between DR6cp (a member of the TNF receptor family
that mediate cell apoptosis) and ARA267-a fragment
containing four PHD and one SET conserved domains
may occur, suggesting a possible cross-talk between
the apoptosis signaling pathway and the androgen
signaling pathway [24–26].
ART-27
Art-27, a small protein of 157 aminoacids and
with molecular weight of 18 kDa, is a newly identified
AR N-terminal coactivator that increases receptor-
dependent transcriptional activity. It seems to interact
predominantly with the AR aminoacids 153–336, con-
taining AF-1a and a part of AF-1b. Art-27 is expressed
in a variety of human tissues sensitive to androgen
action such as prostate, breast and skeletal muscle.
According to the results of some studies, Art-27 pro-
motes epithelial prostate cell differentiation and inhi-
bits proliferation. In human prostate cancer cells this
protein in not markedly expressed. In LNCaP transfec-
ted cell line, the reintroduction of Art-27 reduced cell
proliferation and upregulated the androgen-mediated
transcription of the PSA gene, a gene that is activated
in differentiated epithelial prostate cells. The mecha-
nism by which Art-27 is regulated is unclear. However,
androgens might not directly control its expression be-
cause of the restricted cell-type distribution of Art-27.
Moreover, addition of androgens in LNCaP cell line did
not induce Art-27 expression. The altered Art-27 ex-
pression during prostate cancer progression should
be an object of further analysis [27–29].
β-Catenin
β-Catenin contains five LXXLL motifs situated in the
central core region containing the armadillo repeats.
This region is required for the β-catenin interaction
with E-cadherin and members of the T-cell factor (TCF)
and lymphoid enhancer factor (LEF) family, thus initia-
ting the transcription of the Wnt/Wingless-responsive
genes [30, 31]. The Wnt/Wingless signaling pathway
apart of its role in regulating cell processes such
as proliferation, polarity and migration, is also involved
in oncogenesis. 80% of colon cancers present elevated
β-catenin-TCF signaling. Moreover, it has been de-
monstrated that β-catenin mutations can occur in more
than 50% of colon cancer cases and in more than 50%
of hepatoblastoma cases. β-catenin mutations were
detected in 5% of prostate cancer tissue samples. Four
of them are located in the serine or theonine residues
implicated in the degradation of β-catenin and one
(the codon 32) changes aspartic acid to a tyrosine.
The mutations occurred focally and therefore should
be considered as a late event in prostate cancer
progression. β-catenin can regulate AR function and
contribute to the prostate cancer progression despite
low levels of endogenous androgens, by modulating
receptor-dependent signaling. In LNCaP cell line,
β-catenin (β-catenin S33F) can relieve the inhibitory
effects of the antiandrogen bicalutamide and increase
the poor action to the androgen androstenedione
on AR transactivation to a level comparable to DHT. Cor-
relation between β-catenin and other steroid receptors
6 Experimental Oncology 31, 3–8, 2009 (March)
is possible: it increases the transcriptional activity of the
retinoic acid receptor [31, 32].
FHL2
Four and a half LIM domains 2 (FHL2), a LIM pro-
tein, is the first tissue-specific co-activator of the AR.
As it was shown for prostate epithelial cell and the
myocardium of the heart, FHL2 is able to enhance the
AR transactivation in an agonist- and AF-2-dependent
manner. The interaction between FHL2 and AR requires
both the N- and C-terminus of the AR. There is also evi-
dence of an interaction between FHL2 and β-catenin.
Although no synergistic action on AR transcriptional
activity was observed in prostatic cell cultures, the
activation of the cyclin D1 promoter is mediated
by FHL2 in a β-catenin dependent manner in liver tu-
mors. It was shown that the Rho signaling pathway
induces activation and nuclear translocation of FHL2,
because AR-dependent genes activation and the the
N-terminal of FHL2 are required for this process. In ad-
dition, Rho GTP-ases overexpression and FHL2 nuclear
localization correlate with a lower differentiation grade
of prostate tumor. Therefore, it would be interesting
to examine the contribution of FHL2 to AR function and
prostate cancer progression [33–36].
Her2/NEU
Her2/Neu, a transmembrane glycoprotein with
intrinsic tyrosine kinase activity, is a member of the epi-
dermal growth factor receptors family (EGFR). Over-
expression of Her2/Neu was found in 30% of breast
and ovarian cancers. Contrasting results of various
studies regarding the Her2/Neu gene product ex-
pression are reported, probably due to differences
in the reagents, lack of standardized techniques and
different scoring methodologies. Moreover, by several
researches a varying degree of Her2/Neu gene ampli-
fication was shown. However, according to the recent
reports, Her2/Neu is implicated in the enhancement
of AR transactivation and progression to an androgen-
resistant stage of prostate cancer [37, 38].
ErbB2 is able to signal in the absence of ligand by di-
merization leading to autophosphorylation and initiation
of specific signal transduction cascades. There are two
known transduction pathways by which Her2/Neu may
lead to androgen-independent prostate cancer: the
PI3K/Akt and the MAPK pathway. The Akt activation was
examined in LNCaP co-trasfected cell line. It was found
that Akt can be activated by Her2/Neu in the absence
of androgens and that Akt can induce AR transactivation
promoting the development of an androgen-indepen-
dent growth of prostate cancer cells [39, 40]. In fact,
growth inhibitory effects were observed when the Akt
inhibitor LY294002 was added. According to the above-
mentioned studies, the amino acids at sites 213 and
791 of the AR are phosphorylated by Akt. In addition,
Akt may increase the PSA transcription by activating
the PSA gene promoter. On the other hand, enhance-
ment of the PSA levels and AR activity induced by Her2/
Neu via the MAPK pathway were detected in LNCaP
and DU145 prostate cancer cell lines. It is possible
that the phosphorylation site(s) of the AR are located
in the hormone-independent N-terminal region. Since
there is evidence that Her2/Neu may be associated
with an androgen-independent prostate cancer, nume-
rous therapeutical molecules targeting this tyrosine
kinase are in trial [39–44]. Trastuzumab (Herceptin),
a monoclonal antibody directed against the extracellular
domain of the Her2/Neu protein, presents antitumor
activity in androgen-independent prostate cancer xe-
nografts. Trastuzumab in association with paclitaxel,
a chemotherapeutic agent, had also high antitumor
properties against androgen-independent prostate
cancer. Other monoclonal antibodies (MDX-H210 with
GM-CSF) have been tested also with positive antipro-
liferative properties in DU145 and PC-3 prostate can-
cer cell lines since Her2/Neu protein expression was
downregulated. Finally, an ansamycin antibiotic, the
17-Allylamino-17-demethoxygeldanamycin (17-AAG),
can cause degradation of Her2/Neu, Akt and AR.
Inhibiting action of 17-AAG was observed in prostate
cancer xenografts.
IL-6
IL-6, a cytokine with pleiotropic functions, plays
an important role in the physiopathology of prostate
cancer. Elevated IL-6 levels in the sera of patients
with prostate cancer are associated with high mortali-
ty, poor prognosis and AR transactivation. IL-6 can
modulate the growth of malignant cells through at least
three distinct signaling pathways including JAK/STAT3,
MAPK and PI3K/Akt [39, 40]. However, until now the
data regarding the effects of IL-6 on prostate can-
cer remain controversial, probably because of the
coexistence of these multiple pathways with either
positive or negative influence on each other. In LNCaP
cells, in the absence of androgens, IL-6 can increase
AR gene expression and activate the AR. In addition,
the application of several MAPK inhibitors blocked the
IL-6- mediated induction of the androgen-responsive
promoter, demonstrating that IL-6 activity depends
on MAPK pathway. Many other studies report growth
stimulating effects of IL-6 [40, 41, 44]. In contrast,
some investigators found that IL-6 inhibits the access
of the coregulator p300 to the complex p160-PSA
promoter with consequent inhibition of histone acety-
lation [45, 46]. They also found that IL-6 inhibited the
PSA gene expression, at least in part, through the
STAT3 pathway without MAPK and PI3K/Akt involve-
ment [46]. The reason for these opposite results
is unknown. One study demonstrated that in LNCaP
cells, IL-6 can induce G1 growth arrest reflected in de-
creasing levels of cyclin-dependent kinase-2 (CDK2),
-4 (CDK4), and -6 (CDK6). In addition, the LNCaP cells
underwent neuroendocrine differentiation. Neuroen-
docrine-like differentiation as a result of treatment with
IL-6 was also observed by another group of scientists
in an LNCaP cell line. Moreover, the scientists found
that androgens-ARs can block neuroendocrine dif-
ferentiation by inhibiting the IL-6 mediated PI3K/Akt
pathway [39–41, 45, 46].
Experimental Oncology 31, 3–8, 2009 (March) 7
CONCLUSION
Growth of the prostate malignant cells highly de-
pends on the androgens presence. ARGA represents
one of the molecular mechanisms involved in the
development of hormone refractory prostate cancer.
AR trancriptional activity is influenced by a number of co-
regulators. Co-activators and co-repressors impair the
AR transcriptional status, which in return affect the whole
process of prostate carcinogenesis. ARA54, ARA55,
ARA70, ARA 267-a, ART-27 as well as β-catenin, FHL-2,
Her2/Neu and IL-6, represent the most important and
well-studied co-regulator proteins.
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