Induction of androgen receptor expression by phosphatidylinositol 3-kinase/Akt downstream substrate, FOXO3a, and their roles in apoptosis of LNCaP prostate cancer cells *
Induction of androgen receptor expression by phosphatidylinositol 3-kinase/Akt downstream substrate, FOXO3a, and their roles in apoptosis of LNCaP prostate cancer cells *
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DOI：
10.1074/jbc.m504461200
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发表时间：
2005-09-30
影响因子：
4.8
通讯作者：
Chang, CS
中科院分区：
文献类型：
--
作者：
Yang, L;Xie, SZ;Chang, CS
磷脂酰肌醇3-激酶(PI3K)/Akt通路在前列腺癌细胞存活中起重要作用，雄激素受体（AR）在前列腺癌细胞增殖中起重要作用。然而，这两种信号如何协同控制细胞生长和死亡仍然不清楚和有争议。本研究通过鉴定叉头转录因子FOXO3a （PI3K/Akt下游底物）作为诱导AR基因表达的正调节因子，提供了首个链接。Western blot和real - time PCR均证实FOXO3a可在蛋白和mRNA水平诱导AR表达，凝胶移位和染色质免疫沉淀实验进一步证实FOXO3a可通过结合AR 5‘启动子- 1290至- 1297 （5’- ttgtttca -3‘）的一致dna结合序列诱导5’ AR启动子活性。在正常生长条件下，LY294002阻断PI3K/Akt信号可使LNCaP细胞阻滞在G(1)期而非凋亡。然而，AR小干扰RNA进一步阻断AR功能会导致LNCaP细胞急剧死亡，这表明当LY294002阻断PI3K/Akt信号通路时，AR可能发挥重要的保护作用。总之，我们的数据提供了第一个解释正常条件下PI3K/Akt和AR如何协同控制LNCaP细胞生长和死亡的模型。
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays important roles for prostate cancer cell survival, and the androgen receptor (AR) plays essential roles for prostate cancer cell proliferation. How these two signals cooperate to control cell growth and death, however, remains unclear and debated. Here we provide the first linkage by the identification of Forkhead transcription factor FOXO3a, the PI3K/Akt downstream substrate, as a positive regulator for the induction of AR gene expression. Both Western blot and real time PCR assays demonstrate that FOXO3a can induce AR expression at the protein and mRNA levels, and gel shift and chromatin immunoprecipitation assays further demonstrate that FOXO3a can induce 5' AR promoter activity via binding to the consensus DNA-binding sequence in the AR 5' promoter - 1290 to - 1297 (5'-TTGTTTCA-3'). Under normal growth conditions, blocking PI3K/Akt signals by LY294002 causes LNCaP cell arrest in G(1) phase rather than apoptosis. However, further blocking of AR functions by AR small interfering RNA leads to dramatic LNCaP cell death, suggesting that AR may play important protective roles when the PI3K/Akt signal pathway is blocked by LY294002. Together, our data provide the first model to explain how PI3K/Akt and AR can cooperate to control LNCaP cell growth and death under normal conditions.