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线粒体丙酮酸载体调控肿瘤发生
作者:小柯机器人 发布时间:2019/12/6 11:27:00

美国犹他大学Jared Rutter和Carl S. Thummel团队合作发现,线粒体丙酮酸载体调控肿瘤发生。这一研究成果2019年12月5日发表在《细胞—代谢》上。

尽管已经证明代谢适应对于肿瘤细胞增殖是必不可少的,但是对肿瘤发生的代谢基础知之甚少。研究人员发现,结肠直肠癌(CRC)发生的最早阶段是由糖酵解代谢特征标记的,包括线粒体丙酮酸载体(MPC)的下调,后者通过线粒体丙酮酸的输入结合了糖酵解和葡萄糖氧化。果蝇的遗传研究表明,这种下调是必需的,因为肠道干细胞中Apc或Notch肿瘤抑制因子的丧失引起的畸形增长可被MPC过表达完全阻断。

此外,在两种不同的CRC小鼠模型中,在致瘤性刺激之前Mpc1的丢失使腺瘤形成的频率增加了一倍,并产生了更高级别的肿瘤。MPC丢失与糖酵解代谢表型和干细胞标志物表达增加有关。这些数据表明,细胞丙酮酸代谢的改变对于促进肿瘤发生是必要和充分的。

附:英文原文

Title: Regulation of Tumor Initiation by the Mitochondrial Pyruvate Carrier

Author: Claire L. Bensard, Dona R. Wisidigama, Kristofor A. Olson, Jordan A. Berg, Nathan M. Krah, John C. Schell, Sara M. Nowinski, Sarah Fogarty, Alex J. Bott, Peng Wei, Katja K. Dove, Jason M. Tanner, Vanja Panic, Ahmad Cluntun, Sandra Lettlova, Christian S. Earl, David F. Namnath, Karina Vázquez-Arreguín, Claudio J. Villanueva, Dean Tantin, L. Charles Murtaugh, Kimberley J. Evason, Gregory S. Ducker, Carl S. Thummel, Jared Rutter

Issue&Volume: December 05, 2019

Abstract: Although metabolic adaptations have been demonstrated to be essential for tumor cellproliferation, the metabolic underpinnings of tumor initiation are poorly understood.We found that the earliest stages of colorectal cancer (CRC) initiation are markedby a glycolytic metabolic signature, including downregulation of the mitochondrialpyruvate carrier (MPC), which couples glycolysis and glucose oxidation through mitochondrialpyruvate import. Genetic studies in Drosophila suggest that this downregulation is required because hyperplasia caused by loss ofthe Apc or Notch tumor suppressors in intestinal stem cells can be completely blocked by MPC overexpression. Moreover, in two distinct CRC mouse models, loss of Mpc1 prior to a tumorigenic stimulus doubled the frequency of adenoma formation and producedhigher grade tumors. MPC loss was associated with a glycolytic metabolic phenotypeand increased expression of stem cell markers. These data suggest that changes incellular pyruvate metabolism are necessary and sufficient to promote cancer initiation.

DOI: 10.1016/j.cmet.2019.11.002

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30609-6

期刊信息

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx