Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells.
Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells.
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DOI：
10.1038/s41417-021-00326-4
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发表时间：
2022-05
影响因子：
6.4
通讯作者：
Koike, Kazuhiko
中科院分区：
文献类型：
--
作者：
Suzuki, Tatsunori;Kishikawa, Takahiro;Sato, Tatsuyuki;Takeda, Norihiko;Sugiura, Yuki;Seimiya, Takahiro;Sekiba, Kazuma;Ohno, Motoko;Iwata, Takuma;Ishibashi, Rei;Otsuka, Motoyuki;Koike, Kazuhiko
KRAS基因的突变激活发生在几乎所有的胰腺导管腺癌（PDAC）中，是其癌变过程中最早的分子事件。PDAC中存在代谢重编程，如氨基酸稳态和自噬流等。然而，KRAS突变对PDAC癌变早期代谢重编程的生物学效应尚不清楚。在这里，我们报告了永生化人类非癌胰腺导管上皮细胞的动态代谢重编程，其中KRAS突变是通过基因编辑诱导的，这可能模拟早期胰腺癌的发生。与PDAC的情况类似，KRAS基因突变增加了维持细胞内氧化还原平衡对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，细胞需要更大的自噬通量来维持其活力。溶酶体抑制剂氯喹显著抑制细胞增殖。因此，代谢重编程是由KRAS基因突变启动的癌发生的早期事件，这表明开发抑制或延迟PDAC发展的营养干预措施的基本原理。
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.
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