Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters.
Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters.
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DOI：
10.18632/oncotarget.9006
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发表时间：
2016-06-07
期刊：
影响因子：
--
通讯作者：
Ronen SM
中科院分区：
文献类型：
--
作者：
Viswanath P;Najac C;Izquierdo-Garcia JL;Pankov A;Hong C;Eriksson P;Costello JF;Pieper RO;Ronen SM
异柠檬酸脱氢酶1（IDH 1）突变是低级别胶质瘤的特征。我们最近发现突变IDH 1细胞通过下调丙酮酸脱氢酶（PDH）活性来重编程细胞代谢。通过PDH减少丙酮酸代谢可导致丙酮酸转化为乳酸的增加。因此，本研究的目的是研究IDH 1突变对乳酸-乳酸通量的影响。我们使用13 C磁共振波谱，并比较了表达突变型或野生型IDH 1（NHAIDHmut和NHAIDHwt）的永生化正常人星形胶质细胞中超极化[1 - 13 C]-丙酮酸向[1- 13 C]-乳酸的转化。我们的结果表明，与NHAIDHwt相比，NHAIDHmut细胞中超极化乳酸盐的产生减少。这种减少与NHAIDHmut细胞中单羧酸转运蛋白MCT 1和MCT 4的较低表达相关。此外，NHAIDHmut和NHAIDHwt细胞的裂解物中超极化乳酸盐产生相当，其中MCT不影响超极化丙酮酸盐递送和乳酸盐产生。总的来说，我们的研究结果表明，较低的MCT表达是NHAIDHmut细胞中超极化乳酸产生较低的关键因素。在NHAIDHmut细胞中，SLC 16 A3（MCT 4）启动子而非SLC 16 A1（MCT 1）启动子被高甲基化，这表明可能存在不同的介导MCT表达降低的机制。最后，对来自癌症基因组图谱的低级别胶质瘤患者活检数据的分析显示，与野生型相比，突变型IDH 1肿瘤中的MCT 1和MCT 4表达显著降低。总之，我们的研究表明，减少MCT表达是突变IDH 1胶质瘤代谢重编程的一部分。这一发现可能会影响治疗，并对突变IDH 1胶质瘤的代谢成像具有重要意义。
Mutations in isocitrate dehydrogenase 1 (IDH1) are characteristic of low-grade gliomas. We recently showed that mutant IDH1 cells reprogram cellular metabolism by down-regulating pyruvate dehydrogenase (PDH) activity. Reduced pyruvate metabolism via PDH could lead to increased pyruvate conversion to lactate. The goal of this study was therefore to investigate the impact of the IDH1 mutation on the pyruvate-to-lactate flux. We used 13C magnetic resonance spectroscopy and compared the conversion of hyperpolarized [1-13C]-pyruvate to [1-13C]-lactate in immortalized normal human astrocytes expressing mutant or wild-type IDH1 (NHAIDHmut and NHAIDHwt). Our results indicate that hyperpolarized lactate production is reduced in NHAIDHmut cells compared to NHAIDHwt. This reduction was associated with lower expression of the monocarboxylate transporters MCT1 and MCT4 in NHAIDHmut cells. Furthermore, hyperpolarized lactate production was comparable in lysates of NHAIDHmut and NHAIDHwt cells, wherein MCTs do not impact hyperpolarized pyruvate delivery and lactate production. Collectively, our findings indicated that lower MCT expression was a key contributor to lower hyperpolarized lactate production in NHAIDHmut cells. The SLC16A3 (MCT4) promoter but not SLC16A1 (MCT1) promoter was hypermethylated in NHAIDHmut cells, pointing to possibly different mechanisms mediating reduced MCT expression. Finally analysis of low-grade glioma patient biopsy data from The Cancer Genome Atlas revealed that MCT1 and MCT4 expression was significantly reduced in mutant IDH1 tumors compared to wild-type. Taken together, our study shows that reduced MCT expression is part of the metabolic reprogramming of mutant IDH1 gliomas. This finding could impact treatment and has important implications for metabolic imaging of mutant IDH1 gliomas.
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影响因子：
4.3
作者：
Draoui N;Feron O
通讯作者：
Feron O
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
5.7
作者：
Bola BM;Chadwick AL;Michopoulos F;Blount KG;Telfer BA;Williams KJ;Smith PD;Critchlow SE;Stratford IJ
通讯作者：
Stratford IJ
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1056/nejmoa1407279
发表时间：
2015-06-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Eckel-Passow JE;Lachance DH;Molinaro AM;Walsh KM;Decker PA;Sicotte H;Pekmezci M;Rice T;Kosel ML;Smirnov IV;Sarkar G;Caron AA;Kollmeyer TM;Praska CE;Chada AR;Halder C;Hansen HM;McCoy LS;Bracci PM;Marshall R;Zheng S;Reis GF;Pico AR;O'Neill BP;Buckner JC;Giannini C;Huse JT;Perry A;Tihan T;Berger MS;Chang SM;Prados MD;Wiemels J;Wiencke JK;Wrensch MR;Jenkins RB
通讯作者：
Jenkins RB