sirna-directed in vivo silencing of androgen receptor inhibits the growth of castration-resistant prostate carcinomassirna-directed体内雄激素受体的沉默抑制castration-resistant前列腺癌的生长.pdfVIP

SIRNA-Directed In Vivo Silencing of Androgen Receptor Inhibits the Growth of Castration-Resistant Prostate Carcinomas 1. 1. ´ 1. ` 1 1 2 2 Daniel Compagno , Carole Merle , Aurelie Morin , Cristele Gilbert , Jacques R. R. Mathieu , Aline Bozec , Claire Mauduit , Mohammed 2 1 Benahmed , Florence Cabon * ´ 1 CNRS, University Paris-Sud, FRE2944, Epigenetics and Cancer, Institut Andre Lwoff, Villejuif, France, 2 INSERM U406, Lyon, France Background. Prostate carcinomas are initially dependent on androgens, and castration or androgen antagonists inhibit their growth. After some time though, tumors become resistant and recur with a poor prognosis. The majority of resistant tumors still expresses a functional androgen receptor (AR), frequently amplified or mutated. Methodology/Principal Findings. To test the hypothesis that AR is not only expressed, but is still a key therapeutic target in advanced carcinomas, we injected siRNA targeting AR into mice bearing exponentially growing castration-resistant tumors. Quantification of siRNA into tumors and mouse tissues demonstrated their efficient uptake. This uptake silenced AR in the prostate, testes and tumors. AR silencing in tumors strongly inhibited their growth, and importantly, also markedly repressed the VEGF production and angiogenesis. Conclusions/Significance. Our results demonstrate that carcinomas resistant to hormonal manipulations still depend on the expression of the androgen receptor for their development in vivo. The siRNA-directed silencing of AR, which allows targeting overexpressed as well as mutated isoforms, triggers a strong antitumoral and antiangiogenic effect. siRNA-directed silencing of this key gene in advanced and resistant pros