Abstract A major clinical problem with PC (prostate cancer) is the cell&apos;s ability to survive and proliferate upon androgen withdrawal. Indeed, deregulated cell differentiation and proliferation, together with the suppression of apoptosis, provides the condition for abnormal tissue growth. Here, we examine the differential role of TRP (transient receptor potential) channels in the control of Ca 2+ homoeostasis and growth of PC cells

G Bidaux

M Flourakis

N Prevarskaya

R Skryma

S Thebault

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Cell and Molecular Biology of TRP Channels 133
Differential role of TRP channels in
prostate cancer
N. Prevarskaya*†1, M. Flourakis*†, G. Bidaux*†, S. Thebault*† and R. Skryma*†
*Inserm, U-800, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d’Ascq F-59655, France, and †USTL (Université des Sciences et
Technologies de Lille), Villeneuve d’Ascq F-59655, France
Abstract
A major clinical problem with PC (prostate cancer) is the cell’s ability to survive and proliferate upon androgen
withdrawal. Indeed, deregulated cell differentiation and proliferation, together with the suppression of
apoptosis, provides the condition for abnormal tissue growth. Here, we examine the differential role of TRP
(transient receptor potential) channels in the control of Ca2+ homoeostasis and growth of PC cells.
Introduction
PC (prostate cancer) is one of the leading threats to men’s
health. Its early stage depends on androgens for growth and
survival, and androgen ablation therapy may at this time be
effective in causing tumours to regress; however, in the late
androgen-independent stage there is currently no successful
therapy. It is, therefore, vital to understand what drives the
progression to androgen independence. The latter is asso-
ciated with the appearance of new cell phenotypes, charac-
terized by apoptosis inhibition and aberrant cell proliferation.
Deregulated cell differentiation and proliferation together
with the suppression of apoptosis provides the conditions
for abnormal tissue growth, which ultimately can turn into
uncontrolled expansion and invasion characteristics of cancer.
The role of calcium (Ca2+) in the overall cancer-related
cell signalling pathways is uncontested. Alterations in Ca2+
homoeostasis have been described to increase proliferation
[1,2] and to induce differentiation [3] or apoptosis [4–6].
According to a growing number of studies, cationic channels
in the TRP (transient receptor potential) family are key
players of calcium homoeostasis and cell physiopathology.
In the last few years, it has emerged that several members
of the TRP family could play an important role in prostate
carcinogenesis and, moreover, some of them have been
suggested as prognostic markers for PC, with particular use
in differential diagnosis [6].
Here, we examine the differential role of TRP channels in
Ca2+ homoeostasis of PC epithelial cells and their respective
role in prostate carcinogenesis. Recent progress achieved in
our understanding of molecular mechanisms of TRP channel
signalling involved in the control of PC progression ensures
Key words: apoptosis, calcium, cell differentiation, cell proliferation, prostate cancer, transient
receptor potential channel (TRP channel).
Abbreviations used: AR, adrenergic receptor; ER, endoplasmic reticulum; IP3, inositol
trisphosphate; LNCaP, lymph node carcinoma of the prostate; NFAT, nuclear factor of activated
T-cells; PC, prostate cancer; PM, plasma membrane; siRNA, small interfering RNA; TRP, transient
receptor potential; TRPC, TRP canonical; TRPM8, TRP melastatin 8; ERTRPM8, ER TRPM8; PMTRPM8,
PM TRPM8.
1To whom correspondence should be addressed (email Natacha.Prevarskaya@univ-
lille1.fr).
that sooner or later fundamental breakthroughs will progress
to practical applications.
Agonist-dependent growth regulation of
human PC epithelial cells: the role of TRPC
(TRP canonical) channels
Various growth factors, neurotransmitters and hormones,
known to control physiological and pathological cell prolifer-
ation, participate in the maintenance of intracellular Ca2+
homoeostasis. Although the nature of these agonists has yet
to be well established during PC progression, they invariably
induce a Ca2+ entry called agonist-induced Ca2+ entry. Using
the androgen-dependent LNCaP (lymph node carcinoma
of the prostate) cell line and primary cultures of human PC
epithelial cells established from resection specimens, we have
demonstrated that α1-AR (α1-adrenergic receptor) stimul-
ation activates non-specific cationic channels, leading to
agonist-induced Ca2+ entry [7].
Interestingly, we have also shown that in contrast with the
stimulatory role of α1-ARs in PC cell growth, metabotropic
purinergic receptors (P2Y-R) are involved in the growth
arrest of human PC cells [8]. Such divergent effects of two
receptors on cell proliferation are surprising, since both
α1-AR and P2Y-R are known to be coupled with the common
phospholipase C-catalysed inositol phospholipids break-
down signalling pathway, via which α1-agonists and extra-
cellular ATP could apparently induce similar increases in
[Ca2+]i (intracellular free Ca2+). The opposite effects on
cell proliferation can only be explained if the agonist-indu-
ced Ca2+ entry controlled by each receptor utilizes different
Ca2+-permeable membrane channels ultimately destined to
target various intracellular effectors. We have shown that the
pattern of Ca2+ signalling initiated by α1-AR stimulation is
characterized by regular oscillatory activity, which is almost
exclusively based on the Ca2+ entry pathway directly gated
by DAG (diacylglycerol) with no apparent role for IP3 (in-
ositol trisphosphate)-mediated store depletion. In contrast,
Ca2+ signalling coupled with P2Y-R stimulation is largely
determined by IP3-mediated store-dependent processes,
C©2007 Biochemical Society
134 Biochemical Society Transactions (2007) Volume 35, part 1
Figure 1 Schematic diagram showing in simplified form differential TRPM8 localization and function dependence on androgen receptor
(AR) activity of human prostate epithelial cells and on their differentiation status
including robust Ca2+ release and the activation of store-
operated Ca2+ influx.
Our results highlight the importance of Ca2+ entry path-
ways in the discrimination of the signalling via α1-ARs and
P2Y-purinergic receptors in hPCE cells. Indeed, the α1-AR
agonists activate Ca2+ entry mainly via the TRPC6 channel,
whereas ATP-evoked Ca2+ entry predominantly involves
TRPC1 and TRPC4 channels. TRPC6 silencing by antisense
hybrid depletion or by siRNA (small interfering RNA)
decreased both hPCE cell proliferation and agonist-induced
Ca2+ entry. In contrast, agonist-induced Ca2+ entry and
related growth arrest associated with P2Y-R stimulation in-
volved neither TRPC6 nor NFAT (nuclear factor of activated
T-cells). Thus the TRPC6 channel (which determines the
oscillatory pattern of Ca2+ signalling coupling the agonist-
mediated α1-AR stimulation with Ca2+-dependent activation
of the NFAT transcription factor) could potentially represent
a suitable target for therapeutic intervention.
TRPM8 (TRP melastatin 8) localization and
function in prostate depends on the
differentiation status: role in
carcinogenesis
TRPM8 is a so-called ‘cold’ receptor belonging to the mela-
statin (TRPM) subfamily of TRP channels and is activated
by cooling temperatures and menthol. Aside from sensory
neurons, in which the role of TRPM8 in mediating cold-
evoked excitation is fairly well established [9,10], this channel
is most abundantly expressed in the prostate. In fact, TRPM8
was first cloned from the human prostate as a prostate-specific
gene [11], even before its role in the cold sensation was es-
tablished. Moreover, while remaining at moderate levels in
normal prostate, TRPM8 expression strongly increases in PC.
Despite the growing number of studies, the role of TRPM8
in prostate remains unclear, and it has been suggested to
be involved in secretion function of the prostate and in the
regulation of proliferation and/or apoptosis [12,13].
It has been also shown that anti-androgen therapy greatly
reduced the expression of TRPM8, suggesting that TRPM8
is regulated by androgens [14]. We have demonstrated that in
PC cell lines, and in primary cultures of normal, hyperplasic
and cancerous prostate epithelial cells, TRPM8 is a target gene
of the androgen receptor [12]. TRPM8 expression-silenc-
ing experiments using siRNA suggest that the Ca2+ inflow
through TRPM8 plays an essential role in cellular Ca2+
homoeostasis in prostate epithelial cells and is involved in
cell survival [13].
Our results [15] and those of Zhang and Barritt [13] indi-
cate that TRPM8 may be expressed not just in the PM (plasma
membrane), but also in the ER (endoplasmic reticulum)
C©2007 Biochemical Society
Cell and Molecular Biology of TRP Channels 135
membrane. Dual localization and channel-like function of
TRPM8 in the two membranes significantly broaden the
spectrum of physiological and pathological processes it may
be involved in. However, the mechanisms that determine
the preferred localization of TRPM8 in cells of different
phenotypes are not known so far. Our results demonstrate
that only highly differentiated human prostate primary
luminal epithelial cells express functional PM [PMTRPM8
(PM TRPM8)] channels. Moreover, prostate epithelium
cancer cells (obtained from in situ PCs) were characterized by
significantly larger PMTRPM8-mediated current density than
normal cells. We have shown that this PMTRPM8 activity
was abolished in dedifferentiated cells that had lost their
luminal secretory phenotype. However, we found that, in
contrast with PMTRPM8, ERTRPM8 (ER TRPM8) remained
functional (as an ER Ca2+ release channel), independently
of its differentiation status. Furthermore, similarly to
dedifferentiated prostate epithelial cells, metastatic, LNCaP
cells also exhibited most exclusive TRPM8 localization in the
ER [15]. We hypothesize (Figure 1) that in prostate, TRPM8
localization may depend on epithelial cell phenotype (i.e. fully
differentiated secretory apical cells versus non-differentiated
basal cells) and on androgen status (i.e. androgen-dependent
versus hormone refractory cells highly resistant to apoptosis).
Taken together, these results suggest that TRPM8 may
contribute to the initiation, promotion and progression of
carcinogenesis in prostate epithelial cells.
This work was supported by grants from Inserm, Ministère de
l’Education, La Ligue Nationale Contre le Cancer and the region Nord/
Pas-de-Calais.
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Received 29 August 2006
C©2007 Biochemical Society


Differential role of TRP channels in prostate cancer

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Differential role of TRP channels in prostate cancer

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