Feuerecker Benedikt, Biechl Philipp, Veltkamp Christian, Saur Dieter, Eisenreich Wolfgang
Department of Nuclear Medicine, School of Medicine, Technische Universität München, 81675 Munich, Germany.
German Cancer Consortium (DKTK), Partner Site München, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Metabolites. 2021 May 30;11(6):350. doi: 10.3390/metabo11060350.
In modern oncology, the analysis and evaluation of treatment response are still challenging. Hence, we used a C-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-C]glucose, the effects of DCA treatment in the core carbon metabolism were analyzed in these cells using gas chromatography-mass spectrometry (GC/MS). C-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-C]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.
在现代肿瘤学中，治疗反应的分析和评估仍然具有挑战性。因此，我们采用一种基于碳（C）的方法来研究小分子二氯乙酸（DCA）对胰腺癌细胞代谢反应的影响。分别用75 mM DCA处理两种不同的由致癌性PI3K驱动的胰腺癌细胞系9580和10158，处理18小时。在存在[U-¹³C]葡萄糖的情况下，使用气相色谱-质谱联用仪（GC/MS）分析DCA处理对这些细胞核心碳代谢的影响。关键氨基酸的¹³C富集和同位素异构体谱显示DCA处理对葡萄糖代谢有显著影响。对这两种胰腺癌细胞系进行DCA处理后，在处理过的癌细胞中，[U-¹³C]葡萄糖掺入丙氨酸、天冬氨酸、谷氨酸、甘氨酸、脯氨酸和丝氨酸的量显著降低，而未处理的癌细胞中则没有这种现象。对于这两种细胞系，数据表明丙酮酸脱氢酶有一定程度的激活，通过三羧酸循环的碳通量增加，但糖酵解通量和氨基酸生物合成也受到大量抑制，推测是通过抑制PI3K/Akt/mTORC轴实现的。总体而言，更详细地研究DCA引导或辅助的癌症治疗中的早期治疗反应似乎是值得的，因为这可能为改进癌症的诊断和治疗方案开辟新途径。
