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Abstract
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.
Highlights
Metabolic reprogramming is an essential hallmark of cancer [1, 2]
Comparison of the build-up of hyperpolarized lactate over www.impactjournals.com/oncotarget time showed a clear reduction in hyperpolarized lactate production in NHAIDHmut cells relative to NHAIDHwt (Figure 1B)
Our results indicated that MCT1 expression was reduced by 33.3±6.4% (p
Summary
Metabolic reprogramming is an essential hallmark of cancer [1, 2]. A common feature of many types of cancer cells is the phenomenon of aerobic glycolysis, known as the Warburg effect [7, 8]. In the presence of oxygen, normal differentiated cells metabolize glucose to pyruvate through glycolysis followed by oxidation of pyruvate via the tricarboxylic acid (TCA) cycle. On the other hand, metabolize glucose mostly to lactate, even under aerobic conditions [9]. To avoid the associated reduction in intracellular pH and resultant cellular death, cancer www.impactjournals.com/oncotarget cells up-regulate expression of several transporters including the monocarboxylate transporters 1 and 4 (MCT1 and MCT4) [10,11,12,13]
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