补骨脂素通过雄激素受体相关信号通路对前列腺癌细胞增殖的抑制作用及其机制研究

It has been demonstrated that androgen receptor (AR) plays an important role on the development and progress of prostate cancer (PCa). AR related signaling pathways have become the focus of prostate investigation. As a nature anti-tumor active ingredient, psoralen attracts a wide spread attention for its inhibitory effect on many malignant tumors. However, no study concerning the effect of psoralen on PCa has been reported. In our previous study, psoralen was shown to have a significant inhibitory effect on cell proliferation of LNCaP-AI cell lines. This inhibitory effect could be interrupted when the AR expression of LNCaP-AI cells was silenced by transient transfection of siRNA. Base on these findings, we made a hypothesis that psoralen may have inhibitory effect on the proliferation of AR positive prostate cancer cells via the androgen receptor related signaling pathways. The present study plans to further identify the inhibitory effect of psoralen on the proliferation of androgen independent PCa cells; to design and the phosphorylation protein array according to known AR signaling pathways, to screen the AR signaling pathways associated to the inhibitory effect of psoralen on LNCaP-AI cell proliferation using the cell cycle PCR array and the phosphorylation protein array, and to validate the revealed signaling pathways both in vitro and in vivo. We aim to explore the molecular mechanism underlying the inhibitory effect of psoralen on LNCaP-AI cell proliferation via AR related signaling pathways, as well as the clinical value of psoralen for the treatment of androgen independent PCa. Our study will provide the theoretical foundation for the development of the new drug for androgen independent PCa.

雄激素受体（AR）在前列腺癌（PCa）的发生发展中起重要作用，AR信号通路一直是PCa研究的重点。补骨脂素是抗肿瘤天然药物活性成分，因对多种恶性肿瘤有抑制作用而越来越受到关注，但其在PCa的作用未见报道。我们前期研究发现补骨脂素可显著抑制PCa细胞株LNCaP-AI增殖；通过siRNA干扰LNCaP-AI的AR表达后，补骨脂素的抑制作用可被阻断。我们据此推测补骨脂素可能通过AR相关信号通路抑制AR阳性PCa细胞增殖。本研究拟进一步明确补骨脂素对雄激素非依赖性PCa细胞增殖能力和细胞分裂周期的影响；根据已知AR信号通路设计磷酸化蛋白芯片，结合细胞周期PCR芯片，筛选与补骨脂素抑制LNCaP-AI细胞增殖相关的AR信号通路,并在体内外验证，以探索补骨脂素通过AR信号通路抑制LNCaP-AI细胞增殖的分子机制，探讨补骨脂素在雄激素抵抗性PCa中的临床价值，为开发PCa的新型治疗药物提供理论基础。

补骨脂素是抗肿瘤天然药物活性成分，因对多种恶性肿瘤有抑制作用而越来越受到关注，但其在PCa的作用研究甚少。我们通过体外实验明确了补骨脂素可显著抑制PCa细胞株LNCaP-AD、LNCaP-AI、PC3增殖，作用呈浓度-时间依赖性；体内实验证实补骨脂素可显著抑制裸鼠前列腺癌移植瘤生长；流式细胞仪检测发现补骨脂素可将LNCaP-AD、LNCaP-AI、PC3细胞阻滞于G0/G1、G2/M期；明确了补骨脂素对前列腺癌细胞雄激素受体、雌激素受体β、PCNA、Ki67等基因表达的影响；通过mRNA+lnRNA基因芯片技术筛选出了补骨脂素抑制雄激素非依赖性前列腺癌细胞的相关基因与信号传导通路。本课题深入探讨了补骨脂素对雄激素非依赖性前列腺癌细胞的抑制作用及其作用机制，可为补骨脂素治疗去势抵抗性前列腺癌的临床应用提供实验依据，为开发前列腺癌的新型治疗药物提供理论基础。