Inhibition of the Androgen Receptor as a Novel Mechanism of Taxol Chemotherapy in Prostate Cancer

被引:161
作者
Gan, Lu [1 ,2 ]
Chen, Shuai [1 ,2 ]
Wang, Yuwei [3 ]
Watahiki, Akira [3 ]
Bohrer, Laura [1 ,2 ]
Sun, Zhen [1 ,2 ]
Wang, Yuzhuo [3 ,4 ]
Huang, Haojie [1 ,2 ]
机构
[1] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA
[3] BC Canc Agcy, Dept Canc Endocrinol, Vancouver, BC, Canada
[4] Univ British Columbia, Dept Urol Sci, Prostate Ctr, Vancouver, BC V5Z 1M9, Canada
基金
加拿大健康研究院;
关键词
CELLS; PACLITAXEL; FOXO1; PHOSPHORYLATION; MITOXANTRONE; PROGRESSION; PREDNISONE; RESISTANCE; DOCETAXEL; KINASE;
D O I
10.1158/0008-5472.CAN-09-1504
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 AIL 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. [Cancer Res 2009; 69(21):8386-94]
引用
收藏
页码:8386 / 8394
页数:9
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