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Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway

谷氨酰胺 柠檬酸循环 代谢途径 生物化学 生物 谷氨酸脱氢酶 柠檬酸合酶 谷氨酰胺分解 癌细胞 谷氨酰胺酶 三羧酸 癌症 化学 细胞生物学 氨基酸 谷氨酸受体 遗传学 受体
作者
Jaekyoung Son,Costas A. Lyssiotis,Haoqiang Ying,Xiaoxu Wang,Sujun Hua,Matteo Ligorio,Rushika M. Perera,Cristina R. Ferrone,Edouard Mullarky,Ng Shyh‐Chang,Ya’an Kang,Jason B. Fleming,Nabeel Bardeesy,John M. Asara,Marcia C. Haigis,Ronald A. DePinho,Lewis C. Cantley,Alec C. Kimmelman
出处
期刊:Nature [Springer Nature]
卷期号:496 (7443): 101-105 被引量:1686
标识
DOI:10.1038/nature12040
摘要

Pancreatic cancers use a novel glutamine metabolism pathway, regulated by oncogenic KRAS, to maintain redox balance; these findings add to the understanding of the mechanisms by which oncogenic alterations reprogram cellular metabolism to promote tumour growth. Pancreatic tumours often carry activating KRAS mutations. This study describes a novel KRAS-regulated pathway that is critical to the metabolism of glutamine by human pancreatic cancer cells and is required for tumour growth. The pathway appears to maintain redox homeostasis but is dispensable in normal cells, providing a possible avenue for pursuing antitumour compounds that might act in pancreatic ductal adenocarcinoma, an extremely aggressive cancer that is highly refractory to chemotherapy, radiation and targeted therapies. Cancer cells have metabolic dependencies that distinguish them from their normal counterparts1. Among these dependencies is an increased use of the amino acid glutamine to fuel anabolic processes2. Indeed, the spectrum of glutamine-dependent tumours and the mechanisms whereby glutamine supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumour growth. Whereas most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derived glutamate into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP+ ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumours.
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