Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines.
Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines.
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DOI：
10.18632/oncotarget.3723
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发表时间：
2015-05-20
期刊：
影响因子：
--
通讯作者：
Bovée JV
中科院分区：
文献类型：
--
作者：
Suijker J;Oosting J;Koornneef A;Struys EA;Salomons GS;Schaap FG;Waaijer CJ;Wijers-Koster PM;Briaire-de Bruijn IH;Haazen L;Riester SM;Dudakovic A;Danen E;Cleton-Jansen AM;van Wijnen AJ;Bovée JV
异柠檬酸脱氢酶1（IDH 1）和IDH 2的突变在良性和恶性软骨肿瘤，神经胶质瘤和白血病的子集中发现。该突变酶导致D-2-羟基戊二酸（D-2-HG）的产生，影响CpG岛和组蛋白甲基化。虽然IDH 1/2突变是良性软骨肿瘤的早期事件，但我们评估了这些突变是否在恶性软骨肉瘤中起作用。与IDH 1/2野生型细胞系相比，携带内源性IDH 1（n=3）或IDH 2突变（n=2）的软骨肉瘤细胞系显示细胞内和细胞外D-2-HG水平增加高达100倍。使用AGI-5198特异性抑制突变体IDH 1以剂量依赖性方式降低D-2-HG水平。在处理72小时后，三个突变IDHl细胞系中的一个显示出活力的中度降低，而D-2-HG水平降低> 90%。同样，长时间处理（最多20代）不影响增殖和迁移。此外，整体基因表达，CpG岛甲基化以及组蛋白H3 K4，-9和-27三甲基化水平保持不变。因此，虽然IDH 1/2突变导致内生软骨瘤，但向中央软骨肉瘤的恶性进展使软骨肉瘤的生长独立于这些突变。因此，基于抑制突变IDH 1的单一疗法似乎不足以治疗不能手术或转移的软骨肉瘤患者。
Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found in a subset of benign and malignant cartilage tumors, gliomas and leukaemias. The mutant enzyme causes the production of D-2-hydroxyglutarate (D-2-HG), affecting CpG island and histone methylation. While mutations in IDH1/2 are early events in benign cartilage tumors, we evaluated whether these mutations play a role in malignant chondrosarcomas. Compared to IDH1/2 wildtype cell lines, chondrosarcoma cell lines harboring an endogenous IDH1 (n=3) or IDH2 mutation (n=2) showed up to a 100-fold increase in intracellular and extracellular D-2-HG levels. Specific inhibition of mutant IDH1 using AGI-5198 decreased levels of D-2-HG in a dose dependent manner. After 72 hours of treatment one out of three mutant IDH1 cell lines showed a moderate decrease in viability, while D-2-HG levels decreased >90%. Likewise, prolonged treatment (up to 20 passages) did not affect proliferation and migration. Furthermore, global gene expression, CpG island methylation as well as histone H3K4, -9, and -27 trimethylation levels remained unchanged. Thus, while IDH1/2 mutations cause enchondroma, malignant progression towards central chondrosarcoma renders chondrosarcoma growth independent of these mutations. Thus, monotherapy based on inhibition of mutant IDH1 appears insufficient for treatment of inoperable or metastasized chondrosarcoma patients.
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影响因子：
16.6
作者：
Guilhamon P;Eskandarpour M;Halai D;Wilson GA;Feber A;Teschendorff AE;Gomez V;Hergovich A;Tirabosco R;Fernanda Amary M;Baumhoer D;Jundt G;Ross MT;Flanagan AM;Beck S
通讯作者：
Beck S
影响因子：
12.7
作者：
Hartmann, Christian;Meyer, Jochen;von Deimling, Andreas
通讯作者：
von Deimling, Andreas
影响因子：
64.8
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Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
10.5
作者：
Lu C;Venneti S;Akalin A;Fang F;Ward PS;Dematteo RG;Intlekofer AM;Chen C;Ye J;Hameed M;Nafa K;Agaram NP;Cross JR;Khanin R;Mason CE;Healey JH;Lowe SW;Schwartz GK;Melnick A;Thompson CB
通讯作者：
Thompson CB
影响因子：
14.9
作者：
McCarthy DJ;Chen Y;Smyth GK
通讯作者：
Smyth GK