Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States [1]
To investigate the biological effects of KRAS mutation in human pancreatic non-cancerous epithelial cells, we introduced using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system in a G12V mutation in the KRAS gene in Human normal pancreatic epithelial (HPNE) cells, an immortalized human pancreatic primary epithelial cell line
KRAS mutation increased the dependency on glucose and glutamine for energy production and maintenance of the redox balance in human non-cancerous pancreatic cells
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States [1]. The 5-year survival rate of patients with PDAC is 9% [1] and it is predicted that PDAC will, in the near future, become the second leading cause of cancer-related death [2]. The development of interventions that interrupt carcinogenesis will require an understanding of the early biological events during PDAC carcinogenesis
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