In pancreatic ductal adenocarcinoma (PDAC), metabolic rewiring and resistance to standard therapy are closely associated. PDAC cells show enormous requirements for glucose‐derived citrate, the first rate‐limiting metabolite in the synthesis of new lipids. Both the expression and activity of citrate synthase (CS) are extraordinarily upregulated in PDAC. However, no previous relationship between gemcitabine response and citrate metabolism has been documented in pancreatic cancer. Here, we report for the first time that pharmacological doses of vitamin C are capable of exerting an inhibitory action on the activity of CS, reducing glucose‐derived citrate levels. Moreover, ascorbate targets citrate metabolism towards the de novo lipogenesis pathway, impairing fatty acid synthase (FASN) and ATP citrate lyase (ACLY) expression. Lowered citrate availability was found to be directly associated with diminished proliferation and, remarkably, enhanced gemcitabine response. Moreover, the deregulated citrate‐derived lipogenic pathway correlated with a remarkable decrease in extracellular pH through inhibition of lactate dehydrogenase (LDH) and overall reduced glycolytic metabolism. Modulation of citric acid metabolism in highly chemoresistant pancreatic adenocarcinoma, through molecules such as vitamin C, could be considered as a future clinical option to improve patient response to standard chemotherapy regimens.

中文翻译：

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维生素 C 依赖性柠檬酸代谢途径下调可增强胰腺导管腺癌生长停滞

在胰腺导管腺癌（PDAC）中，代谢重新布线和对标准治疗的耐药性密切相关。PDAC 细胞对葡萄糖衍生的柠檬酸盐有巨大的需求，柠檬酸盐是新脂质合成中的第一个限速代谢物。PDAC 中柠檬酸合酶 (CS) 的表达和活性均显着上调。然而，此前在胰腺癌中尚未记录到吉西他滨反应与柠檬酸盐代谢之间的关系。在这里，我们首次报道药理学剂量的维生素 C 能够对 CS 的活性产生抑制作用，降低葡萄糖衍生的柠檬酸盐水平。此外，抗坏血酸的目标是柠檬酸代谢从头脂肪生成途径，损害脂肪酸合酶（FASN）和 ATP 柠檬酸裂解酶（ACLY）的表达。研究发现柠檬酸盐利用率降低与增殖减少直接相关，并且显着地与吉西他滨反应增强相关。此外，柠檬酸衍生的脂肪生成途径的失调与通过抑制乳酸脱氢酶（LDH）和总体糖酵解代谢减少而导致的细胞外pH值显着降低相关。通过维生素 C 等分子调节高度化疗耐药的胰腺腺癌中的柠檬酸代谢，可被视为未来改善患者对标准化疗方案反应的临床选择。