Department of Biochemistry and Molecular Biology, Institute of Genetic Science, Center for Chronic Metabolic Disease Research, Brain Korea 21 Project for Medical Science, Yonsei University, College of Medicine, Seodaemungu, Seoul, Korea.
Biochem J. 2011 Jan 1;433(1):225-33. doi: 10.1042/BJ20101104.
Up-regulation of lipogenesis by androgen is one of the most characteristic metabolic features of LNCaP prostate cancer cells. The present study revealed that androgen increases glucose utilization for de novo lipogenesis in LNCaP cells through the activation of HK2 (hexokinase 2) and activation of the cardiac isoform of PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase). Activation of PKA (cAMP-dependent protein kinase) by androgen increased phosphorylation of CREB [CRE (cAMP-response element)-binding protein], which in turn bound to CRE on the promoter of the HK2 gene resulting in transcriptional activation of the HK2 gene. Up-regulation of PFKFB2 expression was mediated by the direct binding of ligand-activated androgen receptor to the PFKFB2 promoter. The activated PI3K (phosphoinositide 3-kinase)/Akt signalling pathway in LNCaP cells contributes to the phosphorylation of PFKFB2 at Ser466 and Ser483, resulting in the constitutive activation of PFK-2 (6-phosphofructo-2-kinase) activity. Glucose uptake and lipogenesis were severely blocked by knocking-down of PFKFB2 using siRNA (small interfering RNA) or by inhibition of PFK-2 activity with LY294002 treatment. Taken together, our results suggest that the induction of de novo lipid synthesis by androgen requires the transcriptional up-regulation of HK2 and PFKFB2, and phosphorylation of PFKFB2 generated by the PI3K/Akt signalling pathway to supply the source for lipogenesis from glucose in prostate cancer cells.
雄激素上调脂肪生成是 LNCaP 前列腺癌细胞最具特征性的代谢特征之一。本研究揭示，雄激素通过激活 HK2（己糖激酶 2）和激活 PFKFB2 的心脏同工型（6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶），增加 LNCaP 细胞从头脂肪生成的葡萄糖利用。雄激素激活的 PKA（cAMP 依赖性蛋白激酶）增加了 CREB（cAMP 反应元件结合蛋白）的磷酸化，后者反过来与 HK2 基因启动子上的 CRE 结合，导致 HK2 基因的转录激活。PFKFB2 表达的上调是通过配体激活的雄激素受体与 PFKFB2 启动子的直接结合介导的。LNCaP 细胞中激活的 PI3K（磷酸肌醇 3-激酶）/Akt 信号通路有助于 PFKFB2 在 Ser466 和 Ser483 处的磷酸化，导致 PFK-2（6-磷酸果糖-2-激酶）活性的组成型激活。用 siRNA（小干扰 RNA）敲低 PFKFB2 或用 LY294002 抑制 PFK-2 活性严重阻断了葡萄糖摄取和脂肪生成。总之，我们的结果表明，雄激素诱导的从头脂质合成需要 HK2 和 PFKFB2 的转录上调，以及由 PI3K/Akt 信号通路产生的 PFKFB2 磷酸化，为前列腺癌细胞中葡萄糖来源的脂肪生成提供来源。
