54 research outputs found
Nouveaux mécanismes de régulation de la concentration calcique réticulaire : implication dans la physiopathologie de la prostate humaine.
No full textProstate cancer is the second cancer-related cause of decease. Nowadays, treatments aim at decreasing the androgen action on this organ. Unfortunately, with time, patients develop an androgen-independent cancer with fatal issue. Calcium (Ca2+), an ubiquitary second messenger, is involved in several processes such as apoptosis and proliferation. Endoplasmic Reticulum (ER) is a major actor in Ca2+ signalling. Thus, the study of ER channels is critical for developing new therapeutic strategies. Our work led to the identification of two new ER proteins: the translocon and TRPM8 channel (Transient Receptor Potential Melastatin 8). These two channels could represent fundamental elements of calcium signalisation by regulating Ca2+ concentration in the ER. Moreover, the study of Ca2+ signature evolution during prostate carcinogenesis led us to show that Orai1 (identified here as the main carrier of capacitative Ca2+ entry) expression is decreased in advanced prostate cancer. Reversely, TRPV6 (Transient Receptor Potential Vanilloid 6), a Ca2+ channel involved in constitutive Ca2+ entry, is over expressed in prostate cancer later stages. Thus, variations in these proteins expression could be responsible respectively for apoptosis resistance or an increase in prostate cancer cells proliferation. This might explain the evolution of prostate cancer to more aggressive stages.Le cancer de la prostate est la seconde cause de mortalité par cancer chez l'homme. Actuellement, les traitements hormonaux visent à diminuer le taux d'androgènes actifs. Malheureusement, avec le temps, les patients développent un cancer androgènes dont l'issue est fatale. Le calcium (Ca2+), second messager ubiquitaire, est impliqué dans de nombreux processus tels que l'apoptose ou la prolifération. Le Réticulum Endoplasmique (RE) est un acteur essentiel de la signalisation calcique. Ainsi, l'étude de canaux calciques réticulaires est fondamentale dans le développement de nouvelles stratégies thérapeutiques. Les travaux effectués ont permis d'identifier deux nouvelles protéines sur le RE : le translocon et le canal TRPM8 (Transient Receptor Potential Melastatin 8). Ces deux protéines seraient des éléments majeurs de la signalisation calcique en régulant la concentration de Ca2+ du RE. Par ailleurs, l'étude de l'évolution de la signature calcique au cours de la cancérogenèse prostatique a permis de mettre en évidence qu'Orai1 (identifié ici comme étant la protéine responsable de l'Entrée Capacitive de Ca2+) est moins exprimée dans les cancers les plus agressifs. A l'opposé, TRPV6 (Transient receptor potential Vanilloid 6), canal calcique impliqué dans l'entrée constitutive de Ca2+, est surexprimé dans des stades avancés de cancer. Ainsi, les variations d'expression de ces protéines seraient responsables respectivement d'un défaut d'apoptose ou d'une augmentation de la prolifération des cellules cancéreuses prostatiques androgéno-indépendantes. Ceci permettrait d'expliquer l'évolution du cancer de la prostate vers des stades plus agressifs
Insights into Ca(2+) homeostasis of advanced prostate cancer cells.
No full textInternational audienceProstate cancer is the second cancer-related cause of death. Nowadays, the aim of treatments is to decrease the effects of androgens on this organ. Unfortunately, over time, patients develop an androgen-independent cancer with a fatal outcome. The main features of late stage prostate cancer are an increased cell proliferation and apoptosis resistance. It is well known that calcium (Ca(2+)), a ubiquitous secondary messenger, is involved in several processes such as apoptosis and proliferation. In this mini review, we will focus on the changes in Ca(2+) homeostasis of prostate cancer epithelial cells during prostate cancer evolution
Nouveaux mécanismes de régulation de la concentration calcique réticulaire (implication dans la physiopathologie de la prostate humaine)
No full textLe cancer de la prostate est la seconde cause de mortalité par cancer chez l'homme. Actuellement, les traitements hormonaux visent à diminuer le taux d'androgènes actifs. Malheureusement, avec le temps, les patients développent un cancer androgéno-indépendant dont l'issue est fatale. Le calcium (Ca2+), second messager ubiquitaire, est impliqué dans de nombreux processus tels que l'apoptose ou la prolifération. Le Réticulum Endoplasmique (RE) est un acteur essentiel de la signalisation calcique. Ainsi, l'étude de canaux calciques réticulaires est fondamentale dans le développement de nouvelles stratégies thérapeutiques. Les travaux effectués ont permis d'identifier deux nouvelles protéines sur le RE : le translocon et le canal TRPM8 (Transient Receptor Potential Melastatin 8). Ces deux protéines seraient des éléments majeurs de la signalisation calcique en régulant la concentration de Ca2+ du RE. Par ailleurs, l'étude de l'évolution de la signature calcique au cours de la cancérogenèse prostatique a permis de mettre en évidence qu'Orail (identifié ici comme étant la protéine responsable de l'Entrée Capacitive de Ca2+) est moins exprimée dans les cancers les plus agressifs. A l'opposé, TRPV6 (Transient receptor potential Vanilloid 6), canal calcique impliqué dans l'entrée constitutive de Ca2+, est surexprimé dans des stades avancés de cancer. Ainsi, les variations d'expression de ces protéines seraient responsables respectivement d'un défaut d'apoptose ou d'une augmentation de la prolifération des cellules cancéreuses prostatiques androgéno-indépendantes. Ceci permettrait d'expliquer l'évolution du cancer de la prostate vers des stades plus agressifsLILLE1-BU (590092102) / SudocSudocFranceF
TRPV6 channel controls prostate cancer cell proliferation via Ca(2+)/NFAT-dependent pathways.: Role of TRPV6 in prostate cancer
No full textInternational audienceThe transient receptor potential channel, subfamily V, member 6 (TRPV6), is strongly expressed in advanced prostate cancer and significantly correlates with the Gleason >7 grading, being undetectable in healthy and benign prostate tissues. However, the role of TRPV6 as a highly Ca(2+)-selective channel in prostate carcinogenesis remains poorly understood. Here, we report that TRPV6 is directly involved in the control of prostate cancer cell (LNCaP cell line) proliferation by decreasing: (i) proliferation rate; (ii) cell accumulation in the S-phase of cell cycle and (iii) proliferating cell nuclear antigen (PCNA) expression. We demonstrate that the Ca(2+) uptake into LNCaP cells is mediated by TRPV6, with the subsequent downstream activation of the nuclear factor of activated T-cell transcription factor (NFAT). TRPV6-mediated Ca(2+) entry is also involved in apoptosis resistance of LNCaP cells. Our results suggest that TRPV6 expression in LNCaP cells is regulated by androgen receptor, however, in a ligand-independent manner. We conclude that the upregulation of TRPV6 Ca(2+) channel in prostate cancer cells may represent a mechanism for maintaining a higher proliferation rate, increasing cell survival and apoptosis resistance as well.Oncogene (2007) 26, 7380-7385; doi:10.1038/sj.onc.1210545; published online 28 May 2007
PSA reduces prostate cancer cell motility by stimulating TRPM8 activity and plasma membrane expression.
No full textInternational audienceAlthough the transient receptor potential melastatin 8 (TRPM8) cold receptor is highly expressed in prostate cancer (PCa) and constitutes a promising diagnostic and prognostic indicator, the natural agonists of this channel in the prostate, as well as its physiological and pathological functions, remain unknown. In this study, we identified the well-known PCa marker, prostate-specific antigen (PSA), as a physiological TRPM8 agonist. Electrophysiological and Ca(2+) imaging studies demonstrated that PSA activated TRPM8-mediated current by the bradykinin 2 receptor signaling pathway. Further investigation of this mechanism by cell-surface biotinylation revealed that the increase in TRPM8 current induced by PSA was due to an increase in the number of functional TRPM8 channels on the plasma membrane. Importantly, wound-healing and migration assays revealed that TRPM8 activation by PSA reduced motility of the PC3 PCa cell line, suggesting that plasma membrane TRPM8 has a protective role in PCa progression. Consequently, PSA was identified as a natural TRPM8 agonist in the prostate and we propose a putative physiological role for both of these proteins in carcinogenesis, making this pathway a potentially important target for anticancer agent development.Oncogene advance online publication, 7 June 2010; doi:10.1038/onc.2010.210
: Ion channels in prostate cancer cells
No full textPlasma membrane ion channels contribute to virtually all basic cellular processes, including such crucial ones for maintaining tissue homeostasis as proliferation, differentiation, and apoptosis. Enhanced proliferation, aberrant differentiation, and impaired ability to die are the prime reasons for abnormal tissue growth, which can eventually turn into uncontrolled expansion and invasion, characteristic of cancer. Prostate cancer (PCa) cells express a variety of plasma membrane ion channels. By providing the influx of essential signaling ions, perturbing intracellular ion concentrations, regulating cell volume, and maintaining membrane potential, PCa cells are critically involved in proliferation, differentiation, and apoptosis. PCa cells of varying metastatic ability can be distinguished by their ion channel characteristics. Increased malignancy and invasiveness of androgen-independent PCa cells is generally associated with the shift to a 'more excitable' phenotype of their plasma membrane. This shift is manifested by the appearance of voltage-gated Na(+) and Ca(2+) channels which contribute to their enhanced apoptotic resistance together with downregulated store-operated Ca(2+) influx, altered expression of different K(+) channels and members of the Transient Receptor Potential (TRP) channel family, and strengthened capability for maintaining volume constancy. The present review examines channel types expressed by PCa cells and their involvement in metastatic behaviors.Cell Death and Differentiation advance online publication, 4 May 2007; doi:10.1038/sj.cdd.4402162
TRPV6 Determines the Effect of Vitamin D3 on Prostate Cancer Cell Growth.
No full textDespite remarkable advances in the therapy and prevention of prostate cancer it is still the second cause of death from cancer in industrialized countries. Many therapies initially shown to be beneficial for the patients were abandoned due to the high drug resistance and the evolution rate of the tumors. One of the prospective therapeutical agents even used in the first stage clinical trials, 1,25-dihydroxyvitamin D3, was shown to be either unpredictable or inefficient in many cases. We have already shown that TRPV6 calcium channel, which is the direct target of 1,25-dihydroxyvitamin D3 receptor, positively controls prostate cancer proliferation and apoptosis resistance (Lehen'kyi et al., Oncogene, 2007). However, how the known 1,25-dihydroxyvitamin D3 antiproliferative effects may be compatible with the upregulation of pro-oncogenic TRPV6 channel remains a mystery. Here we demonstrate that in low steroid conditions 1,25-dihydroxyvitamin D3 upregulates the expression of TRPV6, enhances the proliferation by increasing the number of cells entering into S-phase. We show that these pro-proliferative effects of 1,25-dihydroxyvitamin D3 are directly mediated via the overexpression of TRPV6 channel which increases calcium uptake into LNCaP cells. The apoptosis resistance of androgen-dependent LNCaP cells conferred by TRPV6 channel is drastically inversed when 1,25-dihydroxyvitamin D3 effects were combined with the successful TRPV6 knockdown. In addition, the use of androgen-deficient DU-145 and androgen-insensitive LNCaP C4-2 cell lines allowed to suggest that the ability of 1,25-dihydroxyvitamin D3 to induce the expression of TRPV6 channel is a crucial determinant of the success or failure of 1,25-dihydroxyvitamin D3-based therapies
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