Récepteurs des androgènes constitutivement actifs dans le cancer de la prostate : interconnexions avec les voies de signalisation
MARCIAS, Gemma (2009) Récepteurs des androgènes constitutivement actifs dans le cancer de la prostate : interconnexions avec les voies de signalisation. Thèses de doctorat, Université de Strasbourg.
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The emergence of androgen receptor (AR) mutations is a key event in the progression of prostate cancer (PCa) toward androgen-independency. The AR protein consists in four functional domains: 1) the N-terminal region containing the activation function 1(AF-1) that is responsible for ligand-independent activity of the AR; 2) a central DNA binding domain (DBD) containing two zinc fingers; 3) the hinge region that encompasses a nuclear localization signal (NLS); 4) the C-terminal end (CTE) that includes the ligand binding domain (LBD) and AF-2. Mutations issued from clonal selection conferring new properties to the AR may be involved in PCa progression, bone metastasis and tumour growth under hormonal-treatment. The analysis of human tumour samples from localized and metastatic PCa allowed the identification of a new class of CTE-truncated mutant ARs. These mutant ARs the result of somatic nonsense mutations, and were twenty –fold more frequent in hormone-refractory PCa that in hormone-naïve PCa. Furthermore, recent data proposed aberrant splicing as an alternative mechanism for CTE-truncated ARs. In the present study, we confirmed the coexistence of these two mechanisms, which offers a new preclinical model of hormoneresistant PCa. Investigations on the CTE-truncated Q640X AR have revealed in previous studies the constitutive nuclear localisation and the ligand-independent transcriptional activities of this CTE-truncated AR. Since the AR is a phosphoprotein, we explored the role of kinases signalling pathways in the activity of the Q640X AR. Our present results suggest that this AR mutant requires activating phosphorylation by PI3K/Akt and the MEK1-2 proteins, for full transactivation or transcriptional activities. Furthermore, we demonstrated that serine at position 213 in the AR sequence remains fundamental for signal transduction from PI3K/Akt kinases. In LNCaP cells, we have previously shown that the Q640X AR stimulates transcriptional activities of transcription factors such as NFAT and AP-1. We demonstrate that activation of Phospholipase C is a prerequisite for NFAT activity. In addition, we provide evidence that the crosstalk between truncated AR and NFAT or AP-1 factors depends on upstream signalling pathways. Altogether, our data indicate that Q640X AR requires activating phosphorylation by growth factors signalling pathways for full transcriptional activities. Moreover, this CTE-truncated AR may enhance some ligand/membrane receptors signalling to activate NFAT and AP-1. In conclusion, expression of CTE- truncated ARs may provide a mechanism for resistance to hormonal therapy. Understanding their functional properties ARs will allow the identification of new targeted therapies for the treatment of hormonal resistant PCa. Targeting the PI3K/Akt pathway may be a useful strategy for treating patients with hormone-refractory PCa positive for CTE truncated ARs.
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