Androgen receptor-mTOR crosstalk is regulated by testosterone availability: implication for prostate cancer cell survival.
Androgen receptor-mTOR crosstalk is regulated by testosterone availability: implication for prostate cancer cell survival.
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发表时间：
2010-10
影响因子：
2
通讯作者：
Yue Wu;R. Chhipa;Jinrong Cheng;Haitao Zhang;J. Mohler;C. Ip
中科院分区：
文献类型：
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作者：
Yue Wu;R. Chhipa;Jinrong Cheng;Haitao Zhang;J. Mohler;C. Ip
雄激素受体（AR）和mTOR之间的信号传导可能对前列腺癌细胞耐受雄激素剥夺治疗产生的低雄激素和次优营养条件至关重要。材料和方法在暴露于高或低睾酮的LNCaP细胞中检测AR和mTOR的串扰。AR和mTOR活性分别使用siRNA敲除或特异性化学抑制剂进行修饰。通过对葡萄糖剥夺诱导的细胞死亡的易感性来评估相互通信的生物学意义。结果在睾酮水平低和高的情况下，AR都能正向调节mTOR的活性。mTOR的两个负调节因子TSC1和TSC2可能参与其中，因为它们都被AR敲低而上调。亚基线mTOR增加AR蛋白水平。然而，这种效果只发生在低睾丸激素的情况下。如果在葡萄糖剥夺过程中AR功能受到抑制，则更多的细胞发生凋亡，从而显著降低mTOR活性。结论mTOR信号抑制导致AR功能代偿性增加有利于生存。在雄激素剥夺治疗开始时破坏这个循环可能会延迟，甚至预防前列腺癌的复发。
BACKGROUND Signaling between androgen receptor (AR) and mTOR may be crucial for prostate cancer cells to endure the low androgen and suboptimal nutrient conditions produced by androgen deprivation therapy. MATERIALS AND METHODS AR and mTOR cross-talk was examined in LNCaP cells exposed to either high or low testosterone. AR and mTOR activities were modified separately using either siRNA knockdown or specific chemical inhibitor. The biological significance of the reciprocal communication was assessed by susceptibility to glucose deprivation-induced cell death. RESULTS AR positively regulated mTOR activity in both low and high testosterone levels. TSC1 and TSC2, the two negative regulators of mTOR, may be involved since both were up-regulated by AR knockdown. Sub-baseline mTOR increased AR protein levels. However, this effect only occurred with low testosterone. More cells underwent apoptosis if AR function was inhibited during glucose deprivation, which significantly depressed mTOR activity. CONCLUSION The compensatory increase of AR function due to a repressed mTOR signal is advantageous for survival. Disrupting this loop at the time of initiation of androgen deprivation therapy may delay, or even prevent, the recurrence of prostate cancer.