Androgen receptor levels are upregulated by Akt in prostate cancer.
Androgen receptor levels are upregulated by Akt in prostate cancer.
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DOI：
10.1530/erc-10-0204
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发表时间：
2011-04
影响因子：
3.9
通讯作者：
Logan SK
中科院分区：
文献类型：
--
作者：
Ha S;Ruoff R;Kahoud N;Franke TF;Logan SK
多条证据表明雄激素受体(AR)和丝氨酸/苏氨酸激酶Akt在前列腺癌的发生和发展中存在功能联系。为了研究Akt活性对AR动态平衡的影响，我们用Akt抑制剂处理雄激素依赖的LNCaP和LAPC-4前列腺癌细胞。AKT抑制可降低AR的表达，提示Akt活性是调节AR蛋白水平所必需的。然而，虽然雄激素非依赖性LNCaP-ABL细胞也显示AR蛋白水平在Akt抑制下降低，但雄激素非依赖性LNCaP-AI细胞在类似处理下未能改变AR蛋白水平，这表明这些雄激素非依赖性前列腺细胞中AR蛋白水平是由独立于Akt激活的机制调节的。在体内也观察到了激活Akt下游的AR的调节，当检测到在前列腺中过表达构成活性突变的Myristoylated(MYR)-Akt1的转基因小鼠时。表达活化MYR-Akt1的转基因小鼠表现出更高水平的AR mRNA和蛋白。表达激活的MYR-Akt1不会改变前列腺细胞的生长，当将转基因小鼠与野生型小鼠进行比较时，也没有观察到来自转基因动物的前列腺组织之间的显著大小差异。尽管如此，过量表达Akt的转基因小鼠在前列腺组织中表现出更高水平的γ、H2AX和磷酸化Chk2。这些与癌基因诱导衰老相关的标志物的变化证实了转基因小鼠模型中信号的显著变化。总体而言，本文的结果表明AR水平受Akt途径的调节。
Multiple lines of evidence suggest a functional link between the androgen receptor (AR) and the serine/threonine kinase Akt in the development and progression of prostate cancer. To investigate the impact of Akt activity on AR homeostasis, we treated androgen-dependent LNCaP and LAPC-4 prostate cancer cells with Akt inhibitor. Akt inhibition decreased AR expression, suggesting that Akt activity was required for regulation of AR protein levels. However, while androgen-independent LNCaP-abl cells also showed diminished AR protein levels in response to Akt inhibition, treatment of androgen-independent LNCaP-AI cells failed to alter AR protein levels upon similar treatment, suggesting that AR protein levels in these androgen-independent prostate cells were regulated by mechanisms independent of Akt activation. Regulation of AR, downstream of activated Akt, also was observed in vivo when examining transgenic mice that overexpress constitutively active mutant myristoylated (myr)-Akt1 in the prostate. Transgenic mice animals expressing activated myr-Akt1 exhibited higher levels of AR mRNA and protein. Expression of activated myr-Akt1 did not alter prostate cell growth and no significant size differences between prostate tissues derived from transgenic animals were observed when comparing transgenic to wild-type mice. Still, transgenic mice overexpressing Akt exhibited higher levels of γH2AX and phosphorylated Chk2 in prostate tissue. These changes in markers associated with oncogene-induced senescence confirmed significant altered signaling in the transgenic mouse model. Overall, results presented here suggest that AR levels are regulated by the Akt pathway.