Abstract
Here we analyzed whether the anti-neoplastic effect of carnosine, which inhibits glycolytic ATP production, can be antagonized by ATP production via oxidative phosphorylation fueled by pyruvate. Therefore, glioblastoma cells were cultivated in medium supplemented with glucose, galactose or pyruvate and in the presence or absence of carnosine. CPI-613 was employed to inhibit the entry of pyruvate into the tricarboxylic acid cycle and 2,4-dinitrophenol to inhibit oxidative phosphorylation. Energy metabolism and viability were assessed by cell based assays and histochemistry.ATP in cell lysates and dehydrogenase activity in living cells revealed a strong reduction of viability under the influence of carnosine when cells received glucose or galactose but not in the presence of pyruvate. CPI-613 and 2,4-dinitrophenol reduced viability of cells cultivated in pyruvate, but no effect was seen in the presence of glucose. No effect of carnosine on viability was observed in the presence of glucose and pyruvate even in the presence of 2,4-dinitrophenol or CPI-613.In conclusion, glioblastoma cells produce ATP from pyruvate via the tricarboxylic acid cycle and oxidative phosphorylation in the absence of a glycolytic substrate. In addition, pyruvate attenuates the anti-neoplastic effect of carnosine, even when ATP production via tricarboxylic acid cycle and oxidative phosphorylation is blocked. We also observed an inhibitory effect of carnosine on the tricarboxylic acid cycle and a stimulating effect of 2,4-dinitrophenol on glycolytic ATP production.
Highlights
The anti-neoplastic effect of carnosine has been described for a number of tumor derived cells in vitro including gastric [1, 2], colon [3], ovarian [4] and brain cancer cells [5]
We investigated how the anti-neoplastic effect of carnosine is influenced by the nutritional supply of tumor cells and how glycolysis, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OxPhos) www.impactjournals.com/oncotarget contribute to tumor cell survival
Adding CPI-613 to cells cultivated in glucose results in a small loss of ATP (A3 compared to A1), indicating that a small amount of pyruvate produced by glycolysis is used for mitochondrial ATP production
Summary
The anti-neoplastic effect of carnosine has been described for a number of tumor derived cells in vitro including gastric [1, 2], colon [3], ovarian [4] and brain cancer cells [5]. More recent data point towards variants of glycolytic enzymes that may be expressed in tumors such as pyruvate kinase M2 [15] This knowledge has up to now not resulted in the development of new therapeutic strategies to fight cancer. A thorough investigation of the inhibitory effect of carnosine on tumor cell specific ATP production will greatly help to develop new strategies which can exploit the Warburg effect. This is especially pertinent for malignancies, for those chances of recovery are poor under present-day www.impactjournals.com/oncotarget treatment strategies. The cells were cultivated in the absence and presence of carnosine and we analyzed the influence of pyruvate on carnosine’s anti-neoplastic effect. This appeared to be especially important with regard to serum that was omitted throughout the experiments because it contains compounds of undefined nature
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