Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 75390, USA.
Cell. 2010 Nov 24;143(5):711-24. doi: 10.1016/j.cell.2010.10.010. Epub 2010 Nov 11.
PI3K and PTEN lipid phosphatase control the level of cellular phosphatidylinositol (3,4,5)-trisphosphate, an activator of AKT kinases that promotes cell growth and survival. Mutations activating AKT are commonly observed in human cancers. We report here that ENTPD5, an endoplasmic reticulum (ER) enzyme, is upregulated in cell lines and primary human tumor samples with active AKT. ENTPD5 hydrolyzes UDP to UMP to promote protein N-glycosylation and folding in ER. Knockdown of ENTPD5 in PTEN null cells causes ER stress and loss of growth factor receptors. ENTPD5, together with cytidine monophosphate kinase-1 and adenylate kinase-1, constitute an ATP hydrolysis cycle that converts ATP to AMP, resulting in a compensatory increase in aerobic glycolysis known as the Warburg effect. The growth of PTEN null cells is inhibited both in vitro and in mouse xenograft tumor models. ENTPD5 is therefore an integral part of the PI3K/PTEN regulatory loop and a potential target for anticancer therapy.
PI3K 和 PTEN 脂质磷酸酶控制细胞磷脂酰肌醇 (3,4,5)-三磷酸的水平，该物质是激活 AKT 激酶的激活剂，可促进细胞生长和存活。在人类癌症中，常见 AKT 激活的突变。我们在此报告，ENTPD5，一种内质网 (ER) 酶，在 AKT 活性的细胞系和原发性人类肿瘤样本中上调。ENTPD5 将 UDP 水解为 UMP，以促进 ER 中的蛋白质 N-糖基化和折叠。在 PTEN 缺失细胞中敲低 ENTPD5 会导致内质网应激和生长因子受体丢失。ENTPD5 与胞苷单磷酸激酶-1 和腺苷酸激酶-1 一起构成一个 ATP 水解循环，将 ATP 转化为 AMP，导致有氧糖酵解的代偿性增加，即众所周知的瓦博格效应。PTEN 缺失细胞的体外和小鼠异种移植肿瘤模型中的生长均受到抑制。因此，ENTPD5 是 PI3K/PTEN 调节环的一个组成部分，也是癌症治疗的潜在靶点。
