Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Nobelsväg 16, Stockholm, SE 171 77, Sweden; Department of Biotechnology, Division of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Kladki 24, 80-822 Gdansk, Poland.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Nobelsväg 16, Stockholm, SE 171 77, Sweden.
J Biol Chem. 2011 Dec 2;286(48):41600-41615. doi: 10.1074/jbc.M111.240812. Epub 2011 Aug 23.
Unique sensitivity of tumor cells to the inhibition of glycolysis is a good target for anticancer therapy. Here, we demonstrate that the pharmacologically activated tumor suppressor p53 mediates the inhibition of glycolytic enzymes in cancer cells in vitro and in vivo. We showed that p53 binds to the promoters of metabolic genes and represses their expression, including glucose transporters SLC2A12 (GLUT12) and SLC2A1 (GLUT1). Furthermore, p53-mediated repression of transcription factors c-Myc and HIF1α, key drivers of ATP-generating pathways in tumors, contributed to ATP production block. Inhibition of c-Myc by p53 mediated the ablation of several glycolytic genes in normoxia, whereas in hypoxia down-regulation of HIF1α contributed to this effect. We identified Sp1 as a transcription cofactor cooperating with p53 in the ablation of metabolic genes. Using different approaches, we demonstrated that glycolysis block contributes to the robust induction of apoptosis by p53 in cancer cells. Taken together, our data suggest that tumor-specific reinstatement of p53 function targets the "Achilles heel" of cancer cells (i.e. their dependence on glycolysis), which could contribute to the tumor-selective killing of cancer cells by pharmacologically activated p53.
肿瘤细胞对糖酵解抑制的独特敏感性是抗癌治疗的一个很好的靶点。在这里，我们证明了药理激活的肿瘤抑制因子 p53 在体外和体内介导了癌细胞中糖酵解酶的抑制。我们表明，p53 结合代谢基因的启动子并抑制其表达，包括葡萄糖转运蛋白 SLC2A12（GLUT12）和 SLC2A1（GLUT1）。此外，p53 介导的转录因子 c-Myc 和 HIF1α 的抑制，这些是肿瘤中产生 ATP 的途径的关键驱动因素，有助于 ATP 产生受阻。p53 通过抑制 c-Myc 介导了在常氧条件下几种糖酵解基因的消融，而在缺氧条件下 HIF1α 的下调有助于这种效应。我们确定 Sp1 是与 p53 合作在代谢基因消融中起转录共因子作用的蛋白。我们使用不同的方法证明了糖酵解阻断有助于 p53 在癌细胞中强烈诱导细胞凋亡。总之，我们的数据表明，肿瘤特异性恢复 p53 功能针对了癌细胞的“阿喀琉斯之踵”（即它们对糖酵解的依赖），这可能有助于通过药理激活的 p53 选择性杀死癌细胞。
