The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, Shandong, 266071, P. R. China.
Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310029, P. R. China.
Cancer Commun (Lond). 2020 Sep;40(9):389-394. doi: 10.1002/cac2.12084. Epub 2020 Aug 18.
Highly active lipogenesis is essential for rapid tumor growth. Sterol regulatory element-binding protein (SREBP) is a key transcriptional factor for lipogenesis and activated by reduced sterol and oxysterol levels. However, the mechanism by which cancer cells activate SREBP without altering these sterol/oxysterol levels remains elusive. In one of our recent studies published in Nature entitled "The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis", we demonstrated that activated AKT-mediated phosphoenolpyruvate carboxykinase 1 (PCK1) S90 phosphorylation reduces the gluconeogenic activity of PCK1 and triggers its translocation to the endoplasmic reticulum (ER), where PCK1 acts as a protein kinase and uses GTP, rather than ATP, as a phosphate donor to phosphorylate Insig1/2 thereby reducing oxysterol's binding to Insig1/2 and activating SREBP-mediated lipogenesis for tumor growth. These findings elucidate a coordinated regulation between gluconeogenesis and lipogenesis and uncover a critical role of the protein kinase activity of PCK1 in SREBP-dependent lipid synthesis.
高度活跃的脂肪生成对于肿瘤的快速生长至关重要。固醇调节元件结合蛋白（SREBP）是脂肪生成的关键转录因子，其活性受固醇和氧化固醇水平降低的调节。然而，癌细胞在不改变这些固醇/氧化固醇水平的情况下激活 SREBP 的机制仍然难以捉摸。在我们最近发表在《自然》杂志上的一项题为“糖异生酶 PCK1 通过磷酸化 INSIG1/2 促进脂肪生成”的研究中，我们证明了激活的 AKT 介导的磷酸烯醇丙酮酸羧激酶 1（PCK1）S90 磷酸化降低了 PCK1 的糖异生活性，并触发其向内质网（ER）的易位，在 ER 中，PCK1 作为蛋白激酶，使用 GTP 而不是 ATP 作为磷酸供体来磷酸化 Insig1/2，从而减少氧化固醇与 Insig1/2 的结合，激活 SREBP 介导的脂肪生成以促进肿瘤生长。这些发现阐明了糖异生和脂肪生成之间的协调调节，并揭示了 PCK1 的蛋白激酶活性在 SREBP 依赖性脂质合成中的关键作用。
