Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation.
Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation.
复制标题
DOI：
10.1016/j.celrep.2023.112578
复制
发表时间：
2023-06-27
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
软骨肉瘤是最常见的软骨恶性肿瘤，与异柠檬酸脱氢酶1(IDH1)和IDH2基因的体细胞突变有关。在其良性前体病变-内生性软骨瘤中也发现了IDH体细胞突变，提示IDH突变是恶性转化的早期事件。在我们的研究中研究的人突变型IDH软骨肉瘤和突变型IDH小鼠发展为内生性软骨瘤，显示IDH突变型软骨肉瘤和IDH1突变型小鼠生长板中的突变细胞中仅有糖原沉积。药物阻断糖原利用可引起肿瘤细胞行为、下游能量通路和体内、外肿瘤负荷的改变。突变的胰岛素样生长因子1与低氧诱导因子1α(HIF1α)相互作用，调节糖原代谢关键酶的表达。在这里，我们展示了糖原在内生性软骨瘤和软骨肉瘤中的关键作用，这可能是通过与突变的IDH1和HIF1α的相互作用来调节的。Pathmanapan等人。显示糖原储存在突变的IDH1人软骨肉瘤和突变的IDH1鼠内生软骨瘤发展模型中的肿瘤生长和良性病变形成中的作用。糖原代谢的调节被证明是通过与突变的IDH1和HIF1α的相互作用来调节的。
Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α. Pathmanapan et al. show a role for glycogen stores in tumor growth and benign lesion formation in mutant IDH1 human chondrosarcomas and in a mutant Idh1 murine model of enchondroma development. Regulation of glycogen metabolism was shown to be mediated through an interaction with mutant IDH1 and HIF1α.
登录
查看更多内容
影响因子：
4.3
作者：
Hollander JM;Zeng L
通讯作者：
Zeng L
影响因子：
5.8
作者：
Gelderblom, Hans;Hogendoorn, Pancras C. W.;Bovee, Judith V. M. G.
通讯作者：
Bovee, Judith V. M. G.
DOI：
10.1073/pnas.1424400112
发表时间：
2015-03-03
影响因子：
11.1
作者：
Hirata, Makoto;Sasaki, Masato;Alman, Benjamin A.
通讯作者：
Alman, Benjamin A.
影响因子：
30.8
作者：
Hopyan, S;Gokgoz, N;Alman, BA
通讯作者：
Alman, BA
影响因子：
7.3
作者：
Amary, M. Fernanda;Bacsi, Krisztian;Flanagan, Adrienne M.
通讯作者：
Flanagan, Adrienne M.