Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
Cancer Gene Ther. 2022 May;29(5):505-518. doi: 10.1038/s41417-021-00326-4. Epub 2021 Apr 8.
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.
KRAS 基因突变几乎发生于所有胰腺导管腺癌（PDAC）中，是其癌变过程中的最早分子事件。已有大量证据表明 PDAC 存在代谢重编程，例如氨基酸稳态和自噬通量。然而，KRAS 突变对 PDAC 癌变早期代谢重编程的生物学影响尚不清楚。在这里，我们报告了在永生化的人非恶性胰腺导管上皮细胞中发生的动态代谢重编程，其中通过基因编辑诱导 KRAS 突变，这可能模拟早期胰腺癌发生。与 PDAC 的情况类似，KRAS 基因突变增加了对维持细胞内氧化还原平衡的葡萄糖和谷氨酰胺的依赖性。此外，由于蛋白质合成活跃，细胞内氨基酸水平显著降低，并且细胞需要更大的自噬通量来维持其活力。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的早期事件，这提示了开发营养干预措施的合理性，这些措施可以抑制或延缓 PDAC 的发展。
