Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Cancer Res. 2018 Apr 15;78(8):1972-1985. doi: 10.1158/0008-5472.CAN-17-3155.
Genomic alterations of tumor suppressorsoften encompass collateral protein-coding genes that create therapeutic vulnerability to further inhibition of their paralogs. Here, we report that () is frequently hemizygously codeleted with in gastric cancer. Its isoenzyme ME1 was upregulated to replenish the intracellular reducing equivalent NADPH and to maintain redox homeostasis. Knockdown of ME1 significantly depleted NADPH, induced high levels of reactive oxygen species (ROS), and ultimately cell apoptosis under oxidative stress conditions, such as glucose starvation and anoikis, in ME2-underexpressed cells. Moreover, ME1 promoted tumor growth, lung metastasis, and peritoneal dissemination of gastric cancer Intratumoral injection of siRNA significantly suppressed tumor growth in cell lines and patient-derived xenograft-based models. Mechanistically, was transcriptionally upregulated by ROS in an ETV4-dependent manner. Overexpression of ME1 was associated with shorter overall and disease-free survival in gastric cancer. Altogether, our results shed light on crucial roles of ME1-mediated production of NADPH in gastric cancer growth and metastasis. These findings reveal the role of malic enzyme in growth and metastasis. http://cancerres.aacrjournals.org/content/canres/78/8/1972/F1.large.jpg .
肿瘤抑制因子的基因组改变常常包含旁系蛋白编码基因，这些基因进一步抑制其同源物的功能，从而产生治疗上的脆弱性。在这里，我们报告在胃癌中，()常与 发生半合子缺失。其同工酶 ME1 上调以补充细胞内的还原当量 NADPH，并维持氧化还原稳态。在 ME2 低表达的细胞中，ME1 的敲低显著消耗 NADPH，诱导高水平的活性氧 (ROS)，并在葡萄糖饥饿和失巢凋亡等氧化应激条件下最终导致细胞凋亡。此外，ME1 促进胃癌的肿瘤生长、肺转移和腹膜扩散。在细胞系和基于患者来源异种移植的模型中，肿瘤内注射 siRNA 显著抑制了肿瘤生长。从机制上讲，ROS 以 ETV4 依赖的方式转录上调 。ME1 的过表达与胃癌患者的总生存期和无病生存期较短相关。总的来说，我们的研究结果揭示了 ME1 介导的 NADPH 产生在胃癌生长和转移中的关键作用。这些发现揭示了苹果酸酶在生长和转移中的作用。
