Cancer/Radiothrapie 19 (2015) 220227

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Review article

The androgen receptor for the radiation oncologist

Rcepteur aux andrognes : ce que loncologue radiothrapeute doit savoir
L. Quero a , F. Rozet b , P. Beuzeboc c , C. Hennequin a,
a

Oncologie-radiothrapie, hpital Saint-Louis, 1, avenue Claude-Vellefaux, 75475 Paris, France

Institut mutualiste Montsouris, 42, boulevard Jourdan, 75014 Paris, France
c
Institut Curie, 26, rue dUlm, 75005 Paris, France
b

a r t i c l e

i n f o

Article history:
Received 29 December 2014
Received in revised form 1st February 2015
Accepted 4 February 2015
Keywords:
Prostate cancer
Androgen receptor
Radiotherapy

a b s t r a c t
Androgen deprivation therapy is widely used in combination with radiotherapy for the treatment of
prostate cancer. The knowledge of the biology of the androgen axis could help the radiation oncologist
to combine both modalities in an efcient way. Moreover, new drugs have recently been approved and
their role in combination with radiation needs pre-clinical and clinical studies. This review summarized
the main data on the biology of androgen receptor and the potential implications for the physician.
Mechanisms of interactions between androgen deprivation therapy and radiotherapy are also presented
and discussed.
2015 Socit franaise de radiothrapie oncologique (SFRO). Published by Elsevier Masson SAS. All
rights reserved.

r s u m
Mots cls :
Cancer de la prostate
Rcepteur aux andrognes
Radiothrapie

La suppression andrognique est de plus en plus utilise en association avec la radiothrapie dans le cancer de prostate. La connaissance de la biologie des andrognes peut aider loncologue radiothrapeute
dans le maniement des associations dhormonothrapie et de radiothrapie. En outre, de nouveaux
mdicaments ont t rcemment mis sur le march dans le cadre du cancer de prostate rsistant
la castration. Leur emploi potentiel avec la radiothrapie doit tre valu dans le cadre dtudes prcliniques et cliniques. Cette revue rsume les connaissances acquises sur le rcepteur aux andrognes
et leurs implications potentielles pour le clinicien. Les mcanismes dinteraction entre la suppression
andrognique et la radiothrapie sont galement rsums.
2015 Socit franaise de radiothrapie oncologique (SFRO). Publi par Elsevier Masson SAS. Tous
droits rservs.

1. Introduction
Combination of androgen deprivation therapy and radiotherapy
is now the standard of care for prostate cancers patients of the
high-risk group and some of the intermediate group. If the clinical
benet of this association is now clearly demonstrated, the biological interactions between the hormonal treatment and radiotherapy
are not fully understood. Moreover, new hormonal agents as abiraterone and enzalutamide have been approved for the treatment
of castration-resistant prostate cancers. Their use in earlier phases

Corresponding author.
E-mail address: christophe.hennequin@sls.aphp.fr (C. Hennequin).

of the disease, particularly with radiotherapy, is more and more

discussed.
The aim of this review is to summarize the present knowledge of
the physiology of the androgen receptor and to discuss the potential
interactions between old and new hormonal drugs with radiation.
2. Prostate cancer and androgens
2.1. Prostate cancer biology
Prostate is a gland that synthesizes components of the seminal
uid, including proteases as prostate-specic antigen (PSA). In the
normal adult prostate, the androgen receptor is expressed in all
luminal cells and in some epithelial basal cells as well in stromal
cells.

http://dx.doi.org/10.1016/j.canrad.2015.02.008
1278-3218/ 2015 Socit franaise de radiothrapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.

L. Quero et al. / Cancer/Radiothrapie 19 (2015) 220227

Prostate cancer develops from epithelial cells, but it is not clear

if it arises from basal or luminal cells [1]. However, the role of
stromal cells is essential to promote growth of prostate cancer,
through the secretion of various growth factors. More than 50%
of prostate cancers harbour a gene fusion between the promoter
of transmembrane protease, serine 2 (TMPRSS2) and portions of
the coding regions of E-twenty-six (ETS) transcription factors [2],
mainly erythroblast transformation-specic gene (ERG). TMPRSS2
is an androgen responsive gene (see below). The ETS family members are transcription factors, regulating cell proliferation, cell
migration, cell cycle control and apoptosis [3]. Genomic proling
revealed that mutations in the androgen receptor signalling pathway is much more altered than the others pathways [4].
2.2. Androgen dependency of prostate cancer
Androgen stimulation is fundamental for prostate cancer
growth. Androgen deprivation therapy has demonstrated more
than 60 years ago a dramatic effect on cancer progression [5].
Androgen deprivation therapy is obtained by surgical castration
or by the use of luteinizing hormone-releasing hormone (LH-RH)
agonists or antagonists. Androgen deprivation therapy is supposed
to reduce the serum testosterone level under 0.5 ng/mL. It is still
debated whether a level lower than 0.2 ng/ml improves the clinical
response rate and its duration. Combination of LH-RH agonists and
anti-androgens is called complete androgen blockade: its usefulness was not demonstrated in the treatment of metastatic prostate
cancer. The androgen receptor could induce directly cancer growth,
for example via the TMPRSS2-ETS fusion factor. But it can also cross
talks with numerous growth factors (transforming growth factor
[TGF], vascular endothelial growth factor [VEGF], insulin-like
growth factor [IGF], epithelial growth factor [EGF] and broblast
growth factor [FGF]). For instance, TGF cooperates with androgen receptor signalling to promote stromal cell growth. Androgen
deprivation therapy remains the principal treatment of relapse
after radiotherapy [6].
2.3. Androgens synthesis
Testosterone is the principal circulating androgen and is synthesized by the testis for the major portion. Less than 3% of the
circulating testosterone is bioavailable, most of it being bound
to different proteins, sex hormone-binding protein (SHBG) and
albumin, essentially. The remaining androgens in the bloodstream
(510%) are dehydroepiandrosterone (DHEA), androstenediol and
androstenedione: they are produced by adrenals or by peripheral
conversion of testosterone. Androgens production is regulated by
the hypothalamic-pituitary-gonadal axis. LH-RH is secreted by the
hypothalamus in pulses, thus stimulating luteinizing hormone (LH)
secretion, which acts on Leydig cells in the testis to induce androgen
production. Testosterone acts on hypothalamus through a negative
feedback to prevent LHRH release.
Steroids synthesis begins with mobilization by the steroidogenic acute regulatory protein (StAR) and cleavage by CYP11A1
of cholesterol in pregnenolone (Fig. 1). Subsequent metabolism
to mineralocorticoids, glucocorticoids, androgens or oestrogens
depends of the enzymatic equipment of the tissue. Androgens are
produced from the conversion of pregnenolone-like steroids by the
CYP17, a cytochrome P450 enzyme. CYP17 catalyzes hydroxylase
and lyase reactions: the hydroxylase activity is similar for pregnenolone and progesterone but the lyase activity is much more
potent for 17-OH-pregenolone than 17-OH-progesterone. Hence,
the synthesis of androgens is mainly performed via DHEA. Polymorphisms of the CYP17 gene have been associated with a higher
risk of prostate cancer and a worst prognosis of castration-resistant
prostate cancers [7,8].

221

DHEA and androstenedione, synthesised in adrenal glands, are

transformed in testosterone in the Leydig cells of the testis. Testosterone is released in the bloodstream and enters into the target
cell via passive diffusion through the plasma membrane, but
active transport by organic anion-transport polypeptides have been
described [9]. Testosterone is converted into target tissues (prostate
and a limited number of other tissues) in 5-dihydro-testosterone
by 5-alpha reductase (SRD5A1 or 2). There are two types of 5-alpha
reductase, depending on the target tissue, the type 2 being more
specic for prostatic epithelial cells.
3. The androgen receptor
The androgen receptor is a nuclear transcription factor and is a
member of the steroid receptor superfamily. The androgen receptor gene is located on the X-chromosome at position Xq11-12 and
contains eight exons that encode a protein of 919 amino acids.
Two isoforms of androgen receptor have been described: the predominant isoform B (110 kDa) and the less dominant isoform A
(80 kDa).
Like other members of the nuclear receptor superfamily, the
androgen receptor is composed of four domains (Fig. 2) [10]:
the transcriptional activation domain (exon 1: N-terminal
domain): this domain is necessary and sufcient for transcription activity. It harbours a variable number of highly repetitive
DNA sequences, such as CAG, coding for polyglutamin. The number of CAG repeats is correlated to the transcriptional activity of
the androgen receptor, the shorter CAG repeat length resulting in
a higher transcriptional activity. Racial groups with a high prevalence of prostate cancer had also more frequently a short CAG
repeats, suggesting that early tumorigenesis is dependent on a
more active androgen receptor. The N-terminal domain contains
also coregulators interaction domains;
the DNA-binding domain (exon 2 and 3) with two zinc-nger
regions;
a exible hinge region separates the DNA-binding domain from
the androgen-binding domain: it contains the nuclear localization signal, allowing the androgen receptor to interact with the
cytoskeleton and to migrate to the nucleus, after binding of
importin- [11];
the ligand-binding domain at the C-terminal end (exons 4-8),
containing an androgen-binding pocket.
The activation function AF-1 and AF-2 domains are required
for optimal transactivation. AF-1 undergoes folding when contacted by transcription factor TFIIF after binding of the AR on DNA,
enabling coregulators recruitment. AF2 is a coactivator-binding
site, unmasked after ligand binding.
Ligand-free androgen receptor is sequestered in the cytoplasm
bound to heat-shock proteins (HSP 70, 90 and p23), which protect
it from degradation. After binding of the ligand, a conformational
change of the androgen receptor occurs, which allows dissociation
of heat-shock proteins.
Testosterone and dihydrotestosterone can bind to the androgen receptor, but the latter forms a more stable complex and
is 310 times more potent. Binding of the ligand initiates an
intramolecular interaction between the N-terminal domain and
ligand-binding domain, termed N/C interaction [12]. The androgen receptor becomes phosphorylated and translocates into the
nucleus (Fig. 3). The androgen receptor is phosphorylated at
several sites by different kinases, including mitogen-activated protein kinase (MAPK), protein kinase C (PKC) and protein kinase
B (AKT/PKB). They interact with the androgen receptor, usually
in a ligand-dependent manner. Phosphorylation stabilizes the

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L. Quero et al. / Cancer/Radiothrapie 19 (2015) 220227

Fig. 1. Synthesis of steroids. In blue: classical pathway cholesterol is transformed in pregnenolone, then to dehydroepiandrosterone (DHEA) by cytochrome P450 enzyme
CYP17A1. DHEA is converted to androstenedione through the action of 3-hydroxysteroid dehydrogenase (3HSD) enzymes. 3HSD1 is present in peripheral tissues such as
prostate, skin or breast and is ten-fold more potent than 3HSD2 expressed in adrenal, testes and ovaries. Androstenedione is converted in testosterone by 3HSD3 (testis)
or AKCR1C3 (peripheral tissues). Then 5-dihydro-testosterone (5-DHT) is produced by 5-reductase 1 and 2. In green: Backdoor pathway17-OH-progesterone are acted
on by 5-reductase and aldo-keto reductase 1C (AKR1C) prior to the lyase activity of CYP17A to obtain androsterone, which is converted to androstanediol. An oxidative
step, which could be made by different enzymes (17BHSD 6 or 10, RODH4, RDH5, etc.) is required to convert androstanediol to 5-DHT. In pink: alternative pathway (5androstenedione pathway) androstenedione is converted rst by 5-reductase to 5-androstenedione and then by AKR1C3 (or 17HSD) to 5-DHT, thus circumventing
testosterone as a required intermediate.

ligand/receptor complex and is required for translocation to the

nucleus [13]. The androgen receptor dephosphorylation by the protein phosphatase 2A can lead to loss of its transcriptional activity
[14].
The androgen receptor forms homodimers (and also heterodimers with others proteins) and binds to specic DNA regions,
termed androgen-responsive elements, in association with a series
of transcriptional coregulators. These androgen-responsive elements are located in the promoter regions of target genes and
serve to activate or repress transcription of specic androgenregulated genes. About 146 androgen-regulated genes have been
described [15]. In the mature gland, androgens promote cell division and proliferation of epithelial cells, modulate programmed cell
death, regulate several aspects of prostate cellular metabolism and

control the production of specic proteins such as PSA. For example,

activation of androgen-responsive elements results in an enhanced
expression of cyclin-dependent kinases 2 and 4, down regulation
of the cell cycle inhibitor p16, thereby enhancing cell proliferation.
An up-regulation of p21, an inhibitor of apoptosis, is also observed.
4. Coregulators of the androgen receptor
By denition, these are proteins that increase or inhibit the
transcriptional activity of the androgen receptor [16]. Over 170
coregulators of androgen receptor functions have been identied,
either activators or repressors [17].
Some co-activators, as c-jun or steroid receptor co-activator-2
(src2), bind to the N-terminal domain of the androgen receptor and

Fig. 2. Structure of the androgen receptor and its gene. NTD: N-terminal domain (transcriptional domain); DBD: DNA-binding domain; LBD: ligand-binding domain; AF:
activation function.

L. Quero et al. / Cancer/Radiothrapie 19 (2015) 220227

223

Fig. 3. Androgens and androgen receptor signalling in prostate cancer. Dihydrotestosterone (DHT) binds to the androgen receptor (AR) and promotes its dissociation
from heat-shock protein (HSP). The androgen receptor translocates to the nucleus, dimerizes and binds to androgen-response elements (ARE), activating, with the help of
coactivators (COacT), androgen-regulated genes (ARG).

promote its homodimerization. SRC-2 is overexpressed or amplied

in 11% of prostate cancers [4]. SRC-2 expression is repressed by
androgens and thus, androgen deprivation therapy increases the
SRC-2 level.
Most coregulators are recruited to gene-promoter regions after
binding of androgen receptor dimers on androgen-responsive elements [12]. They function to facilitate or suppress transcription.
Various members of the steroids family can recognize the same
androgen-responsive element. So, the specic response of a tissue
is dependent on the coactivators or repressors. Some coactivators, including SRC-1 and cyclic adenosine monophosphate (cAMP)
response element-binding protein can induce the remodelling of
chromatin by acetylating histones, opening the nucleosomal structure of the gene and allowing the initiation of transcription by RNA
polymerase II.

receptor activation by a low concentration of androgens [19] or by

weak endogenous androgens. The androgen receptor could respond
to non-androgen steroidal hormones as progesterone and estradiol
[20]. Even anti-androgens such as utamide or bicalutamide could
become agonists of the androgen receptor [21]. However, these
mutations are detected in 10 to 20% of cancer specimens and are
responsible of the androgen escape in only a few patients [22,23].
Androgen receptor gene amplication is very common during
the castration-resistant state [24], leading eventually to its overexpression, making tumours cells extremely sensitive to low levels of
circulating androgens. Combined androgen blockade is potentially
a good way to overcome this androgen receptor amplication [25].

5. Mechanisms of castration resistance

Many genes are transcribed with alternative exon usage, and

this is the case for the androgen receptor gene. It has been demonstrated that alternative splicing of the androgen receptor mRNA
could culminate in a receptor that is capable of translocation and
DNA binding without ligand binding [26]. Expression of these variants is correlated with castration resistance [27]. AR-V7 is one of the
best-characterized splice variants, present in castration-resistant
prostate cancers patients [28]: it lacks the ligand-binding domain
and is constitutively active, independently of any androgens. Other
splice variants are required to dimerize with full-length receptors for nuclear translocation and transcriptional activity, and so
remains dependent of androgens [29].
The transcript ARv567es, in which exons 5, 6, and 7 are deleted,
appears to be less dependent of full-length receptors for transcriptional activity. On the other hand, AR-V7 and Arv567es facilitate
full-length receptors nuclear localization in the absence of androgen [30]. It has been recently shown that the presence of this
variant is correlated to abiraterone and enzalutamide resistance
[31]. However, there is at this moment no evidence that these
splice variants are present in localized diseases and in hormonenaive prostate cancers. For locally advanced diseases, when a
combination of androgen deprivation therapy and new

In advanced cancer treated with castration, a clinical and biochemical response is observed in the majority of patients, but
eventually, a resistance state will emerge after a variable delay. Castration resistance is dened as a progression of the disease, either
biological or clinical, with a testosterone level less than 0.5 ng/mL.
Although the exact mechanisms of castration resistance are not
well understood, available data support the physical presence and
activity of the androgen receptor. Castration-resistant prostate cancer is resistant to androgen deprivation therapy but remains often
androgen receptor-dependent [18]. This is evidenced by the usual
rise in serum PSA levels at the time of prostate cancer progression.
5.1. Mutation, amplication or overexpression of the androgen
receptor
In a relatively large proportion of patients with castrationresistant prostate cancers, the androgen receptor is expressed,
overexpressed, mutated or amplied. Mutations of the receptor
have been described, particularly in the ligand-binding domain.
Specicity of the ligand-binding domain could be modify, allowing

5.2. Alternative splicing of the androgen receptor messenger RNA

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L. Quero et al. / Cancer/Radiothrapie 19 (2015) 220227

anti-androgens is considered, looking for this characteristic

could be recommended.
5.3. Alterations of coactivators and others intracellular pathways
Modications of coactivators has also been described: they
could increase the androgen receptor transcriptional activity in the
presence of low ligand concentration or by altering the ligand specicity of the receptor, allowing antiandrogens and estrogens to act as
agonists [32]. ARA70 is often overexpressed in castration-resistant
prostate cancers and facilitates the activation of the androgen
receptor by non-androgenic molecules such as 17-estradiol (E2)
[33]. Interaction of SRC-1 with the androgen receptor results in its
to the same magnitude as that obtained by dihydrotestosterone
[34]. SRC-1 and -2 expression is increased in more than 60% of
castration-resistant prostate cancers. In conclusion, it is clear that
overexpression of androgen receptor coactivators contribute to
prostate cancer progression.
Activation of the androgen receptor could be a consequence of
activating the PI3K/AKT/mTOR pathway via IGF-1, KGF or EGF [35].
The androgen receptor activation can result also by binding of long
non-coding RNAs [36].
5.4. Modications of the androgen synthesis pathways
It has been demonstrated that signicant amount of dihydrotestosterone have been detected in castration-resistant
tumours [37]. Numerous studies suggest that synthesis of androgens occur de novo in castration-resistant prostate cancers. Genes
encoding enzymes involved in androgen metabolism (and particularly CYP17A1) are up regulating in castration-resistant prostate
cancer cells [38]. Testosterone and dihydrotestosterone are usually
produced from cholesterol via the classical pathway in adrenal
glands and testis. However, in castration-resistant prostate cancer
cells, different pathways (backdoor and alternative pathways) are
activated to produce dihydrotestosterone (see Fig. 1) [37,3941].
Intracrine conversion of adrenal weak androgens such as DHEA, 11OH- androstenedione or deoxycorticosterone in steroids activating
the androgen receptor has been also identied [42]. In prostate,
DHEA is rst converted to androstenedione by 3-hydroxysteroid
dehydrogenase (3HSD1). Following castration, adrenal androgen
androstenedione serum and tissue levels are unchanged and a
signicant amount of androstenedione is observed in castrationresistant prostate cancer cells [43]. The alternative pathway seems
to be predominant in these cells [41]. Androstenedione is also
converted in 11-OH-androstenedione by CYP11B1,2 then reduced
in 11-OH-5-dihydrotestosterone by 5-reductase: this molecule
could activate the wild type androgen receptor [44]. All these
enzymes are potential targets for new drugs.
To summarize, four different molecular states of prostate cancer
can be dened [45]:
endocrine androgen-dependent and androgen receptordependent: prostate cancer growth is driven by serum androgens
produced by the testis;
intracrine androgen-dependent and androgen receptordependent: androgens are produced within prostate cancer
cells;
androgen (ligand)-independent and androgen receptordependent: this is the case for androgen receptor variants;
androgen-independent and androgen receptor-independent.
6. New hormonal drugs
In castration-resistant prostate cancers, growth of cancer cells
is often always dependent of the androgen receptor. X-ray

crystallography and computer modelling allow the understanding

of the biochemical interaction between drugs and the androgen
receptor at the atomic level. This helps to design new drugs to
overcome castration resistance.
Residual levels of androgens can be found in cancer cells due
in part to an intratumoral synthesis. Ketoconazole inhibits the 17hydroxylase activities of CYP17A1: at high dose, it has been shown
to obtain PSA response but no survival benet could be demonstrated [46]. Abiraterone acetate (Zytiga ) is an oral irreversible
inhibitor of CYP17A1, one of the major enzymes involved in androgen synthesis (Fig. 3) [47]. CYP17A1 has both 17a-hydroxylase
and 17,20-lyase activities. However, this enzyme is also required
for synthesis of glucocorticoids. Low dose dexamethasone is
required to prevent reexive increase of adrenocorticotropic
hormone (ACTH) and mineralosteroid effects, as hypertension
[48]. Abiraterone acetate decreased the production of androgens
(androstenedione, DHEA, testosterone 5-dihydrotestosterone) by
the adrenal glands, prostate and tumour cells [49].
Clinical trials showed that abiraterone acetate induced a dramatic response in many patients with a castration-resistant
prostate cancers [50]. In a retrospective study, abiraterone acetate
was shown to be superior to ketoconazole in terms of PSA
response and survival [51]. Randomized trials have demonstrated
an improvement in survival in castration-resistant prostate cancers
either after or before docetaxel [52,53].
TAK-700 (orteronel) is an another CYP17A1 inhibitor,
more potent to inhibit CYP17,20 lyase function than CYP17hydroxylase. It does not require an association with prednisone
to prevent mineralocorticoid effects. However, recently presented
phase III studies could not demonstrated an improvement in
survival in castration-resistant prostate cancers and this drug will
be probably not approved by the US Food and Drug Administration
(FDA) and the European Medicines Agency (EMA).
Non-steroidal androgen receptor antagonists, such as utamide
and bicalutamide, have relatively low afnity for the receptor and could, in some cases, become agonists. They do not
inhibit ligand-induced nuclear translocation but recruits nuclear
co-repressors to block androgen-regulated gene transcription
[54]. Enzalutamide (formerly MDV3100-Xtandi ) is eight times
more potent than bicalutamide to inhibit the androgen receptor
[55]; it inhibits not only the binding of testosterone and dihydrotestosterone, but also receptor translocation and binding of
coactivators [56]. Importantly, enzalutamide remains antagonist
of the androgen receptor in overexpressing cells and mutant cell
lines, which convert bicalutamide to an agonist [55]. Enzalutamide
increased overall survival for patients with castration-resistant
prostate cancers either after or before treatment with docetaxel
[57,58].
ARN-509 is an androgen receptor antagonist, differing from
enzalutamide by only one atom [59]. It also prevents androgen
receptor translocation and DNA-binding. Clinical trials are ongoing. Galeterone (TOK-001) inhibits CYP17 at low concentration, but
at higher doses, it could inhibit the androgen receptor and even
facilitates its degradation [60].
All these androgen receptor antagonists are targeting the
ligand-binding domain, which is lost in splice variants. Some new
inhibitors, as EPI-001, are directed against the N-terminal domain
and are supposed to inhibit protein protein interactions [61].
Although abiraterone and enzalutamide provide a survival benet, resistance almost always develops. Several new antiandrogens
agents are being evaluated either in preclinical or clinical studies
[62].
Finally, docetaxel, which inhibits the dissociation of microtubules, prevents nuclear translocation of the androgen receptor
and decreases its intracellular level. Part of its action could be mediated by hormonal inhibition [63,64].

L. Quero et al. / Cancer/Radiothrapie 19 (2015) 220227

7. Interactions between hormonal treatments and

radiation
Androgen deprivation therapy is today the standard hormonal
treatment of prostate cancer. In locally advanced stages, the combination of androgen deprivation therapy and radiotherapy has
demonstrated better survival rates than one modality used alone.
Long-term androgen deprivation therapy is used for high-risk
prostate cancers and short-term therapy for intermediate risk cancers. In contrast with the number of clinical trials involved, only a
few preclinical studies, either in vitro or in vivo, have evaluated the
mechanisms of interaction between hormonal manipulations and
radiations. This could be due to the lack of good preclinical models
for localized disease.
Preclinical models implicated prostate cancer cell lines: some as
LAPC4 or LNCaP are androgen-sensitive, unlike PC3 or DU145 cell
lines which do not expressed the androgen receptor. LNCaP cell
line presents an androgen receptor mutation (T877A LBD), which
allows binding of progesterone or cortisol [65]. LAPC4 cells have a
wild type androgen receptor.
Androgen deprivation therapy by itself induced a major reduction in epithelial cells mainly by apoptosis and decreased cell
proliferation [66]. The LNCaP cell line expressed the androgen
receptor and was regularly used for in vitro studies of combination of androgen deprivation therapy and radiation. Androgen
deprivation therapy was achieved by culture in charcoal-stripped
serum-containing medium. After irradiation, an increase in the
apoptosis rate was observed for LNCaP cultured in medium without
androgens compared to complete medium, but without any difference in clonogenic cell survival, suggesting a shift in the modality
of cell death [67].
Hermann et al. evaluated the effect of goserelin, an LH-RH agonist, on two cell lines, LNCaP et PC3; only LnCaP expressed the
androgen receptor but both cell lines expressed LH-RH receptors, as 86% prostate cancers do [68,69]. No radiosensitization was
observed in both cell lines despite inhibition of the EGF receptor
pathway and cell proliferation.
We have observed that combined treatment with bicalutamide,
an antiandrogen, with radiation concomitantly or sequentially, had
a protective effect over radiation alone in LNCaP cell line. There was
no signicant effect of bicalutamide on DU145 cell line, which does
not expressed the androgen receptor [70]. High levels of bicalutamide had a cytostatic effect on LnCap blocking the cell cycle in
G1 phase; senescence was the main cell death pathway.
In vivo, in different models of prostate cancer xenografts, it
seems that a neoadjuvant androgen deprivation therapy is required
to obtain and maximize the radiosensitizing effect. With the
Shionogi model, Zietman et al. showed that the TCD50 (radiation dose required to control 50% of the tumours) decreased when
androgen deprivation therapy was added to radiation, particularly
if it was given 12 days before irradiation [71]. This effect was correlated to tumour volume regression, suggesting that the decrease
of the number of clonogenic cells explained this supra-additive
effect. In another model, neoadjuvant androgen deprivation therapy (3 days) increased the apoptotic rate compared to radiation
alone or to androgen deprivation therapy given at the same time
than radiation [72]. However, this effect was not found in case of
multiple fractions, suggesting that apoptosis is not the main type
of radiation effect on prostate cancer cells [73]. In a model using
R3327-G dunning rat prostate tumour cells, neoadjuvant androgen
deprivation therapy resulted in prolonged suppression of tumour
growth, compared to irradiation alone or adjuvant androgen deprivation therapy [74].
The number of clonogenic cells, rate of apoptosis but also
hypoxia have been discussed as possible factors of radiosensitivity. Hypoxia is frequent in prostate cancer tissues and maybe also

225

in benign tissues [75,76]. The outcome is negatively inuenced by

hypoxia in patients treated by prostatectomy or radiotherapy [77].
More recently, in a study of 247 patients, in which hypoxia was
measured before radiotherapy, a pO2 10 mmHg was an independent of biochemical control and local control [78].
Inhibition of hypoxia-inducible factor (HIF) 1, the main mediator
of hypoxia, increases the radiosensitivity of PC3 cell line [79]. Looking at the relationship with the androgen axis, hypoxia increases
androgen receptor activation in LNCap cells [80]; HIF1 could be
a coactivator of the androgen receptor [81]. Androgen deprivation therapy decreases the hypoxia-induced expression of VEGF
in androgen-dependent LNCap cell line but not in the androgenindependent PC3 cell line [82]. In Shionogi prostate tumour model,
androgen deprivation therapy decreases the hypoxic fraction from
30 to 2% [83]. Antiandrogens reduce the transcriptional activity
of HIF1 [84]. In one study of 22 patients, hypoxia was measured
using Eppendorf microelectrode technique, androgen deprivation
therapy increased the median pO2 values from 6.4 to 15 mmHg:
part of the radiosensitizing effect of androgen deprivation therapy could be explained by this way [85]. On the other hand, in
a study of 20 patients where dynamic magnetic resonance imaging (MRI) evaluated vascularisation, androgen deprivation therapy
induced a profound reduction in tumour blood ow and an increase
of hypoxia [86].
More recently, it has been demonstrated that ionizing radiations
activated the androgen receptor. Moreover, the androgen receptor upregulated a number of DNA repair genes, particularly genes
of the non-homologous pathway, because these genes contain the
androgen receptor binding sites in their enhancer sequences [87].
In contrast, castration reduced the Ku67 level, a protein essential
for non-homologous end-joining repair of double-strand breaks
[88]. By this way, the androgen receptor promotes radioresistance and androgen deprivation increases DNA-damage and slow
double-strand break repair [89]. New anti-androgen drugs (ARN
509, enzalutamide) enhanced DNA damage and slow repair of DNA
double-strand breaks.
Looking at these results, mechanisms of interaction between
androgen deprivation therapy and radiation are not fully elucidated. New drugs such as abiraterone and enzalutamide give new
opportunities to increase the effect of radiation on prostate cancer.
Preclinical and clinical studies of combination of these drugs with
radiation are urgently needed.
8. Conclusion
The androgen receptor remains the main target of prostate cancer either in locally or advanced disease, in castration dependant
or resistant conditions. Androgen deprivation therapy is an important tool to improve the effect of radiotherapy. The knowledge of
androgen receptor effects is important for the radiation oncologists
to manage at its best the combination of both modalities. New hormonal drugs bring new opportunities to increase the potential of
radiotherapy.
Disclosure of interest
C.H. Occasional involvements: advisory services to Astellas,
Janssen and Ipsen.
L.Q., F.R., P.B. have not supplied their declaration of conict of
interest.
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