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

Cancer cells exhibit metabolic dependencies that distinguish them from their normal counterparts(1). Among these addictions is an increased utilization of the amino acid glutamine (Gln) to fuel anabolic processes(2). Indeed, the spectrum of Gln-dependent tumors and the mechanisms whereby Gln support...

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Autores principales: Son, Jaekyoung, Lyssiotis, Costas A., Ying, Haoqiang, Wang, Xiaoxu, Hua, Sujun, Ligorio, Matteo, Perera, Rushika M., Ferrone, Cristina R., Mullarky, Edouard, Shyh-Chang, Ng, Kang, Ya’an, Fleming, Jason B., Bardeesy, Nabeel, Asara, John M., Haigis, Marcia C., DePinho, Ronald A., Cantley, Lewis C., Kimmelman, Alec C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656466/
https://www.ncbi.nlm.nih.gov/pubmed/23535601
http://dx.doi.org/10.1038/nature12040
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author Son, Jaekyoung
Lyssiotis, Costas A.
Ying, Haoqiang
Wang, Xiaoxu
Hua, Sujun
Ligorio, Matteo
Perera, Rushika M.
Ferrone, Cristina R.
Mullarky, Edouard
Shyh-Chang, Ng
Kang, Ya’an
Fleming, Jason B.
Bardeesy, Nabeel
Asara, John M.
Haigis, Marcia C.
DePinho, Ronald A.
Cantley, Lewis C.
Kimmelman, Alec C.
author_facet Son, Jaekyoung
Lyssiotis, Costas A.
Ying, Haoqiang
Wang, Xiaoxu
Hua, Sujun
Ligorio, Matteo
Perera, Rushika M.
Ferrone, Cristina R.
Mullarky, Edouard
Shyh-Chang, Ng
Kang, Ya’an
Fleming, Jason B.
Bardeesy, Nabeel
Asara, John M.
Haigis, Marcia C.
DePinho, Ronald A.
Cantley, Lewis C.
Kimmelman, Alec C.
author_sort Son, Jaekyoung
collection PubMed
description Cancer cells exhibit metabolic dependencies that distinguish them from their normal counterparts(1). Among these addictions is an increased utilization of the amino acid glutamine (Gln) to fuel anabolic processes(2). Indeed, the spectrum of Gln-dependent tumors and the mechanisms whereby Gln supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of Gln utilization in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumor growth. While most cells utilize glutamate dehydrogenase (GLUD1) to convert Gln-derived glutamate (Glu) into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid (TCA) cycle, PDAC relies on a distinct pathway to fuel the TCA cycle such that Gln-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate (OAA) by aspartate transaminase (GOT1). Subsequently, this OAA 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 Gln 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 Gln metabolism is mediated by oncogenic Kras, the signature genetic alteration in PDAC, via 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 tumors.
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spelling pubmed-36564662013-10-04 Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway Son, Jaekyoung Lyssiotis, Costas A. Ying, Haoqiang Wang, Xiaoxu Hua, Sujun Ligorio, Matteo Perera, Rushika M. Ferrone, Cristina R. Mullarky, Edouard Shyh-Chang, Ng Kang, Ya’an Fleming, Jason B. Bardeesy, Nabeel Asara, John M. Haigis, Marcia C. DePinho, Ronald A. Cantley, Lewis C. Kimmelman, Alec C. Nature Article Cancer cells exhibit metabolic dependencies that distinguish them from their normal counterparts(1). Among these addictions is an increased utilization of the amino acid glutamine (Gln) to fuel anabolic processes(2). Indeed, the spectrum of Gln-dependent tumors and the mechanisms whereby Gln supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of Gln utilization in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumor growth. While most cells utilize glutamate dehydrogenase (GLUD1) to convert Gln-derived glutamate (Glu) into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid (TCA) cycle, PDAC relies on a distinct pathway to fuel the TCA cycle such that Gln-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate (OAA) by aspartate transaminase (GOT1). Subsequently, this OAA 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 Gln 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 Gln metabolism is mediated by oncogenic Kras, the signature genetic alteration in PDAC, via 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 tumors. 2013-03-27 2013-04-04 /pmc/articles/PMC3656466/ /pubmed/23535601 http://dx.doi.org/10.1038/nature12040 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Son, Jaekyoung
Lyssiotis, Costas A.
Ying, Haoqiang
Wang, Xiaoxu
Hua, Sujun
Ligorio, Matteo
Perera, Rushika M.
Ferrone, Cristina R.
Mullarky, Edouard
Shyh-Chang, Ng
Kang, Ya’an
Fleming, Jason B.
Bardeesy, Nabeel
Asara, John M.
Haigis, Marcia C.
DePinho, Ronald A.
Cantley, Lewis C.
Kimmelman, Alec C.
Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway
title Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway
title_full Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway
title_fullStr Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway
title_full_unstemmed Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway
title_short Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway
title_sort glutamine supports pancreatic cancer growth through a kras-regulated metabolic pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656466/
https://www.ncbi.nlm.nih.gov/pubmed/23535601
http://dx.doi.org/10.1038/nature12040
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