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Metabolic Response of Pancreatic Carcinoma Cells under Treatment with Dichloroacetate
Benedikt Feuerecker1,2,3, Philipp Biechl4, Christian Veltkamp5
1Department of Nuclear Medicine, School of Medicine, Technische Universität München, 81675 Munich, Germany.
Abstract:
In modern oncology, the analysis and evaluation of treatment response are still challenging. Hence, we used a 13C-guided approach to study the impacts of the small molecule dichloroacetate (DCA) upon the metabolic response of pancreatic cancer cells. Two different oncogenic PI3K-driven pancreatic cancer cell lines, 9580 and 10,158, respectively, were treated with 75 mM DCA for 18 h. In the presence of [U-13C6]glucose, the effects of DCA treatment in the core carbon metabolism were analyzed in these cells using gas chromatography-mass spectrometry (GC/MS). 13C-enrichments and isotopologue profiles of key amino acids revealed considerable effects of the DCA treatment upon glucose metabolism. The DCA treatment of the two pancreatic cell lines resulted in a significantly decreased incorporation of [U-13C6]glucose into the amino acids alanine, aspartate, glutamate, glycine, proline and serine in treated, but not in untreated, cancer cells. For both cell lines, the data indicated some activation of pyruvate dehydrogenase with increased carbon flux via the TCA cycle, but also massive inhibition of glycolytic flux and amino acid biosynthesis presumably by inhibition of the PI3K/Akt/mTORC axis. Together, it appears worthwhile to study the early treatment response in DCA-guided or accompanied cancer therapy in more detail, since it could open new avenues for improved diagnosis and therapeutic protocols of cancer.
Insights
Dichloroacetate (DCA) significantly alters pancreatic cancer cell metabolism by reducing glucose incorporation into amino acids. This suggests DCA impacts glycolysis and amino acid synthesis, offering potential for new cancer therapies.
Area of Science:
- Metabolomics
- Oncology
- Biochemistry
Background:
- Evaluating treatment response in oncology remains a significant challenge.
- Small molecules like dichloroacetate (DCA) are being investigated for their metabolic effects in cancer.
- Pancreatic cancer cell lines driven by PI3K mutations present a relevant model for metabolic studies.
Purpose of the Study:
- To investigate the metabolic response of pancreatic cancer cells to dichloroacetate (DCA) treatment.
- To analyze the impact of DCA on core carbon metabolism using a 13C-guided approach.
- To evaluate DCA's effects on glucose metabolism and amino acid biosynthesis in PI3K-driven pancreatic cancer cells.
Main Methods:
- Utilized a 13C-guided approach with [U-13C6]glucose to trace metabolic pathways.
- Analyzed metabolic effects in two pancreatic cancer cell lines (9580 and 10,158) treated with DCA.
- Employed gas chromatography-mass spectrometry (GC/MS) to quantify 13C-enrichments and isotopologue profiles of key amino acids.
Main Results:
- DCA treatment significantly decreased the incorporation of 13C-labeled glucose into key amino acids (alanine, aspartate, glutamate, glycine, proline, serine).
- Observed increased carbon flux through the TCA cycle, indicated by pyruvate dehydrogenase activation.
- Demonstrated massive inhibition of glycolytic flux and amino acid biosynthesis, potentially via PI3K/Akt/mTORC axis inhibition.
Conclusions:
- DCA profoundly impacts glucose metabolism and amino acid biosynthesis in pancreatic cancer cells.
- The observed metabolic alterations suggest potential therapeutic strategies involving DCA.
- Further research into early treatment response with DCA could lead to improved cancer diagnostic and therapeutic protocols.
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