二甲双胍抑制STAT3信号增敏bicalutamide对前列腺癌治疗作用研究

研究发现STAT3磷酸化表达升高与前列腺癌恶性程度及预后不良密切相关。以往及我们的前期研究发现，AR RNAi干预或比卡鲁胺处理上调STAT3磷酸化表达水平，但其与去势抵抗前列腺癌（CRPC）关系尚不清楚。进一步研究发现，STAT3信号可增强AR的转录调节，二甲双胍抑制比卡鲁胺导致的STAT3激活，增强对AR转录抑制作用。结合以往及我们前期研究，我们推测前列腺癌细胞存在AR-STAT3-AR反馈信号调节环路，二甲双胍阻断比卡鲁胺诱导的STAT3信号可以抑制或延缓CRPC发生及肿瘤进展。本项目拟分别应用人前列腺癌细胞及TRAMP小鼠前列腺癌动物模型分别研究二甲双胍对AR-STAT3-AR的调节机制及其对比卡鲁胺治疗前列腺癌的增敏作用。该研究结果将揭示CRPC发生新的信号调节机制，为前列腺癌治疗提供研究依据。由于二甲双胍安全性好副作用低，该研究结果也具有重要临床应用价值及社会效益

Androgen-deprivation therapy (ADT) is the standard treatment for metastatic CaP. Athought most prostate cancers are initially dependent on androgen receptor(AR) signaling for cell prliferation and cellular survival and respond well to androgen deprivation therapy.However,many invariably recur with more aggressive castration during such therapy and become resistance to antiandrogen therapy . It is believed that aberrant activation of AR play a crucial role in etiology of castration-resistance prostate cancer. Up to now, the underlying mechanisms remains unknown.. STAT3 has been suggested that to involved that in both prostate cancer progrssion and castration resistance. some investigator found that AR siRNA knockdown could induce STAT3 ctivation.Oure preliminary results also indicated that stronger expression of STAT3 phosphorization was detected in human prosate cancer tissue of the patients treated with neoadjunct therapy before radical prostatectomy. Inhibited STAT3 phosphorzation was also observed in human prostate cancer tissue in vivio treated by neoadjunct therapy or prostate cancer cells in vitro treated bicalutamide. Moreover, metformin could also inhibit STAT3 activated AR transcriptional upregulation by luciferase reporter gene analysis. These obervations collectively suggested that there may exist a unknown feedback signaling mechanism underlying the activated STAT3 is induced by inhibitions of androgen synthesis or AR could enhance AR transcriptioal upregulation. Persistent STAT3 activation may play a key role in AR aberrant activation of CRPC.. In this project, we will examine the effects of metformin on STAT3 phosphorzation and activated STAT3 mediated AR transcriptional regulation as well as its synegistical effeciecy in treatment of prostate cancer. This research will provide new and novel insight into the mechanism underlying the transition of prostate cancer from androgen dependence into androgen independence.Intervention of STAT3 signaling by metformin combined with antiandogen drug (bicalutamide) as new therapeutic approach for overcoming CRPC.