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.
Highlights
Pancreatic cancer is one of the most malignant diseases
pancreatic ductal adenocarcinoma (PDAC) has been reported to develop via acinarductal metaplasia (ADM) and precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), mucinous cystic neoplasia, atypical flat lesions (AFLs) and intraductal papillary mucinous neoplasia (IPMN) [2,3,4]
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Summary
Pancreatic cancer is one of the most malignant diseases. 5-year survival rates remain below 5% [1]. Among the pathways that contribute to PDAC initiation, maintenance and tumor progression, various downstream effectors are affected, such as Raf/Mek/Erk, phosphatidylinositol 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (Pdk1)/Akt, RalGDS/p38MAPK, Rho and Rac, p120GAP [2,9,10]. Genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen-activated protein kinase (MAPK) pathways are implicated in pancreatic cancer [11]. Clinical studies targeting this signaling cascade, were not successful so far [11]
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