Gan Lu, Chen Shuai, Wang Yuwei, Watahiki Akira, Bohrer Laura, Sun Zhen, Wang Yuzhuo, Huang Haojie
Masonic Cancer Center and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Cancer Res. 2009 Nov 1;69(21):8386-94. doi: 10.1158/0008-5472.CAN-09-1504. Epub 2009 Oct 13.
Taxol chemotherapy is one of the few therapeutic options for men with castration-resistant prostate cancer (CRPC). However, the working mechanisms for Taxol are not fully understood. Here, we showed that treatment of 22Rv1, a PTEN-positive CRPC cell line, with paclitaxel and its semisynthetic analogue docetaxel decreases expression of the androgen receptor (AR)-activated genes prostate-specific antigen (PSA) and Nkx3.1 but increases expression of the AR repression gene maspin, suggesting that Taxol treatment inhibits AR activity. This was further supported by the observation that the activity of AR luciferase reporter genes was inhibited by paclitaxel. In contrast, paclitaxel treatment failed to inhibit AR activity in the PTEN-null CRPC cell line C4-2. However, pretreatment of C4-2 cells with the phosphoinositide 3-kinase inhibitor LY294002 restored paclitaxel inhibition of the AR. Treatment of 22Rv1 xenografts in mice with docetaxel induced mitotic arrest and a decrease in PSA expression in tumor cells adjacent to vascular vessels. We further showed that paclitaxel induces nuclear accumulation of FOXO1, a known AR suppressive nuclear factor, and increases the association of FOXO1 with AR proteins in the nucleus. FOXO1 knockdown with small interfering RNA attenuated the inhibitory effect of paclitaxel on AR transcriptional activity, expression of PSA and Nkx3.1, and cell survival. These data reveal a previously uncharacterized, FOXO1-mediated, AR-inhibitory effect of Taxol in CRPC cells that may play an important role in Taxol-mediated inhibition of CRPC growth.
紫杉醇化疗是去势抵抗性前列腺癌（CRPC）男性患者为数不多的治疗选择之一。然而，紫杉醇的作用机制尚未完全明确。在此，我们发现用紫杉醇及其半合成类似物多西他赛处理PTEN阳性的CRPC细胞系22Rv1，会降低雄激素受体（AR）激活基因前列腺特异性抗原（PSA）和Nkx3.1的表达，但会增加AR抑制基因maspin的表达，这表明紫杉醇处理可抑制AR活性。紫杉醇抑制AR荧光素酶报告基因的活性这一观察结果进一步支持了这一点。相比之下，紫杉醇处理未能抑制PTEN缺失的CRPC细胞系C4-2中的AR活性。然而，用磷酸肌醇3激酶抑制剂LY294002预处理C4-2细胞可恢复紫杉醇对AR的抑制作用。用多西他赛处理小鼠体内的22Rv1异种移植物会诱导有丝分裂停滞，并使血管附近肿瘤细胞中的PSA表达降低。我们进一步表明，紫杉醇可诱导已知的AR抑制性核因子FOXO1的核积累，并增加FOXO1与细胞核中AR蛋白的结合。用小干扰RNA敲低FOXO1可减弱紫杉醇对AR转录活性、PSA和Nkx3.1表达以及细胞存活的抑制作用。这些数据揭示了紫杉醇在CRPC细胞中一种以前未被描述的、由FOXO1介导的AR抑制作用，这可能在紫杉醇介导的CRPC生长抑制中发挥重要作用。
