文章：

突变KRAS驱动癌前胰腺细胞的代谢重编程和自噬通量

Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells 

原文发布日期：2021-04-08 

英文摘要：

Mutational activation of the KRAS gene occurs in almost all pancreatic ductal adenocarcinoma (PDAC) and is the earliest molecular event in their carcinogenesis. Evidence has accumulated of the metabolic reprogramming in PDAC, such as amino acid homeostasis and autophagic flux. However, the biological effects of KRAS mutation on metabolic reprogramming at the earlier stages of PDAC carcinogenesis are unclear. Here we report dynamic metabolic reprogramming in immortalized human non-cancerous pancreatic ductal epithelial cells, in which a KRAS mutation was induced by gene-editing, which may mimic early pancreatic carcinogenesis. Similar to the cases of PDAC, KRAS gene mutation increased the dependency on glucose and glutamine for maintaining the intracellular redox balance. In addition, the intracellular levels of amino acids were significantly decreased because of active protein synthesis, and the cells required greater autophagic flux to maintain their viability. The lysosomal inhibitor chloroquine significantly inhibited cell proliferation. Therefore, metabolic reprogramming is an early event in carcinogenesis initiated by KRAS gene mutation, suggesting a rationale for the development of nutritional interventions that suppress or delay the development of PDAC. 

摘要翻译： 

KRAS基因的突变激活发生在几乎所有胰腺导管腺癌（PDAC）中，是其癌变过程中最早的分子事件。目前已有大量证据表明PDAC中存在代谢重编程现象，例如氨基酸稳态和自噬流的变化。然而，在PDAC癌变早期阶段，KRAS突变对代谢重编程的生物学影响尚不明确。本研究报道了在永生化人类非癌性胰腺导管上皮细胞中通过基因编辑诱导KRAS突变后出现的动态代谢重编程现象，该模型可能模拟早期胰腺癌变过程。与PDAC病例相似，KRAS基因突变增加了细胞对葡萄糖和谷氨酰胺的依赖性以维持细胞内氧化还原平衡。此外，由于活跃的蛋白质合成导致细胞内氨基酸水平显著降低，这些细胞需要更强的自噬流来维持其生存能力。溶酶体抑制剂氯喹可显著抑制细胞增殖。因此，代谢重编程是由KRAS基因突变引发的癌变早期事件，这为开发抑制或延缓PDAC发生的营养干预策略提供了理论依据。

原文链接：

Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells