Changes in gene expression in mouse prostate in response to genetic activation of AMPK

Emerging evidence indicates that metabolic dysregulation drives prostate cancer (PCa) progression and metastasis. AMPK is a master regulator of metabolism although its role in PCa remains unclear. Here we show that genetic and pharmacological activation of AMPK provides a dramatic protective effect on PCa progression in vivo. We show that AMPK activation induces PGC1a expression leading to a catabolic metabolic reprogramming of PCa cells. This catabolic state is characterised by increased mitochondrial gene expression, increased fatty acid oxidation, decreased lipogenic potential, decreased cell proliferation and decreased cell invasiveness. Together, these changes inhibit PCa disease progression. Additionally, we identify a gene network that is inhibited by AMPK activation involved in cell cycle regulation. We show correlation between this gene network and PGC1a expression in human PCa. Taken together our findings strongly support the use of AMPK activators for clinical treatment of PCa. RNA from six replicate mouse whole prostate tissue from prostate-specific Pten null and prostate-specific Pten null with AMPK gain-of-function (GoF) mutation was sequenced using NextSeq 500.

越来越多的研究证据表明，代谢失调会驱动前列腺癌（prostate cancer, PCa）的进展与转移。腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK）是代谢的核心调控因子，但其在前列腺癌中的作用仍不明确。本研究发现，AMPK的遗传与药理学激活，可在体内对前列腺癌进展产生显著的保护作用。研究表明，AMPK激活可诱导PGC1α（peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC1α）的表达，进而引发前列腺癌细胞的分解代谢型代谢重编程。此种分解代谢状态的特征为：线粒体基因表达上调、脂肪酸氧化增强、成脂潜能降低、细胞增殖速率下降以及细胞侵袭能力减弱。上述多重变化共同抑制了前列腺癌的疾病进展。此外，本研究还鉴定出一个受AMPK激活抑制、参与细胞周期调控的基因网络。研究证实，该基因网络的表达与人类前列腺癌组织中PGC1α的表达存在相关性。综合以上研究结果，本研究有力支持将AMPK激活剂用于前列腺癌的临床治疗。本研究使用NextSeq 500测序平台，对6份生物学重复的小鼠全前列腺组织RNA进行了测序，这些组织分别来自前列腺特异性PTEN（phosphatase and tensin homolog, PTEN）敲除小鼠，以及同时携带前列腺特异性PTEN敲除与AMPK功能获得（gain-of-function, GoF）突变的小鼠。