Munkley Jennifer, Livermore Karen E, McClurg Urszula L, Kalna Gabriela, Knight Bridget, McCullagh Paul, McGrath John, Crundwell Malcolm, Leung Hing Y, Robson Craig N, Harries Lorna W, Rajan Prabhakar, Elliott David J
Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
Oncoscience. 2015 Sep 14;2(9):755-64. doi: 10.18632/oncoscience.243. eCollection 2015.
Androgen receptor (AR) signalling and the PI3K pathway mediate survival signals in prostate cancer, and have been shown to regulate each other by reciprocal negative feedback, such that inhibition of one activates the other. Understanding the reciprocal regulation of these pathways is important for disease management as tumour cells can adapt and survive when either single pathway is inhibited pharmacologically. We recently carried out genome-wide exon-specific profiling of prostate cancer cells to identify novel androgen-regulated transcriptional events. Here we interrogated this dataset for novel androgen-regulated genes associated with the PI3K pathway. We find that the PI3K regulatory subunits PIK3R1 (p85α) and PIK3R3 (p55γ) are direct targets of the AR which are rapidly repressed by androgens in LNCaP cells. Further characterisation revealed that the PIK3CA p110α catalytic subunit is also indirectly regulated by androgens at the protein level. We show that PIK3R1 mRNA is significantly under-expressed in prostate cancer (PCa) tissue, and provide data to suggest a context-dependent regulatory mechanism whereby repression of the p85α protein by the AR results in destabilisation of the PI3K p110α catalytic subunit and downstream PI3K pathway inhibition that functionally affects the properties of prostate cancer cells.
雄激素受体（AR）信号传导和PI3K通路介导前列腺癌中的生存信号，并且已显示它们通过相互负反馈相互调节，因此抑制其中一个会激活另一个。了解这些通路的相互调节对于疾病管理很重要，因为当任一单通路被药物抑制时，肿瘤细胞都可以适应并存活。我们最近对前列腺癌细胞进行了全基因组外显子特异性分析，以识别新的雄激素调节的转录事件。在此，我们针对与PI3K通路相关的新的雄激素调节基因对该数据集进行了研究。我们发现PI3K调节亚基PIK3R1（p85α）和PIK3R3（p55γ）是AR的直接靶标，在LNCaP细胞中它们会被雄激素迅速抑制。进一步的表征显示，PIK3CA p110α催化亚基在蛋白质水平上也受到雄激素的间接调节。我们表明，PIK3R1 mRNA在前列腺癌（PCa）组织中显著低表达，并提供数据表明存在一种上下文依赖性调节机制，即AR对p85α蛋白的抑制导致PI3K p110α催化亚基不稳定以及下游PI3K通路抑制，从而在功能上影响前列腺癌细胞的特性。
