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A natural inhibitor of kidney-type glutaminase: a withanolide from Physalis pubescens with potent anti-tumor activity

Kidney-type glutaminase (KGA), a mitochondrial enzyme converting glutamine to glutamate for energy supply, was over-expressed in many cancers and had been regarded as a promising therapeutic target in recent years. Structure-based virtual ligand screening predicted physapubescin K, a new withanolide...

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Autores principales: Wu, Canrong, Zheng, Mengzhu, Gao, Suyu, Luan, Shanshan, Cheng, Li, Wang, Liqing, Li, Jiachen, Chen, Lixia, Li, Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768343/
https://www.ncbi.nlm.nih.gov/pubmed/29371926
http://dx.doi.org/10.18632/oncotarget.23058
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author Wu, Canrong
Zheng, Mengzhu
Gao, Suyu
Luan, Shanshan
Cheng, Li
Wang, Liqing
Li, Jiachen
Chen, Lixia
Li, Hua
author_facet Wu, Canrong
Zheng, Mengzhu
Gao, Suyu
Luan, Shanshan
Cheng, Li
Wang, Liqing
Li, Jiachen
Chen, Lixia
Li, Hua
author_sort Wu, Canrong
collection PubMed
description Kidney-type glutaminase (KGA), a mitochondrial enzyme converting glutamine to glutamate for energy supply, was over-expressed in many cancers and had been regarded as a promising therapeutic target in recent years. Structure-based virtual ligand screening predicted physapubescin K, a new withanolide from Physalis pubescens, to be potential KGA inhibitor. Enzyme activity inhibition assays and microscale thermophoresis experiments had demonstrated the efficiency and specificity of physapubescin K targeting KGA. Additionally, physapubescin K exhibited potent proliferation inhibitory effects on a panel of human cancer cell lines, such as SW1990 and HCC827-ER. It blocked glutamine metabolism in SW1990 with increasing intracellular level of glutamine and decreasing glutamate and its downstream metabolites. Physapubescin K also significantly inhibited the tumor growth in a SW1990 xenograft mouse model. Interestingly, physapubescin K could reverse the resistance of HCC827-ER cells to erlotinib and synergize with the hexokinase 2 inhibitor to markedly enhance the inhibition of SW1990 cell proliferation.
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spelling pubmed-57683432018-01-25 A natural inhibitor of kidney-type glutaminase: a withanolide from Physalis pubescens with potent anti-tumor activity Wu, Canrong Zheng, Mengzhu Gao, Suyu Luan, Shanshan Cheng, Li Wang, Liqing Li, Jiachen Chen, Lixia Li, Hua Oncotarget Research Paper Kidney-type glutaminase (KGA), a mitochondrial enzyme converting glutamine to glutamate for energy supply, was over-expressed in many cancers and had been regarded as a promising therapeutic target in recent years. Structure-based virtual ligand screening predicted physapubescin K, a new withanolide from Physalis pubescens, to be potential KGA inhibitor. Enzyme activity inhibition assays and microscale thermophoresis experiments had demonstrated the efficiency and specificity of physapubescin K targeting KGA. Additionally, physapubescin K exhibited potent proliferation inhibitory effects on a panel of human cancer cell lines, such as SW1990 and HCC827-ER. It blocked glutamine metabolism in SW1990 with increasing intracellular level of glutamine and decreasing glutamate and its downstream metabolites. Physapubescin K also significantly inhibited the tumor growth in a SW1990 xenograft mouse model. Interestingly, physapubescin K could reverse the resistance of HCC827-ER cells to erlotinib and synergize with the hexokinase 2 inhibitor to markedly enhance the inhibition of SW1990 cell proliferation. Impact Journals LLC 2017-12-08 /pmc/articles/PMC5768343/ /pubmed/29371926 http://dx.doi.org/10.18632/oncotarget.23058 Text en Copyright: © 2017 Wu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Wu, Canrong
Zheng, Mengzhu
Gao, Suyu
Luan, Shanshan
Cheng, Li
Wang, Liqing
Li, Jiachen
Chen, Lixia
Li, Hua
A natural inhibitor of kidney-type glutaminase: a withanolide from Physalis pubescens with potent anti-tumor activity
title A natural inhibitor of kidney-type glutaminase: a withanolide from Physalis pubescens with potent anti-tumor activity
title_full A natural inhibitor of kidney-type glutaminase: a withanolide from Physalis pubescens with potent anti-tumor activity
title_fullStr A natural inhibitor of kidney-type glutaminase: a withanolide from Physalis pubescens with potent anti-tumor activity
title_full_unstemmed A natural inhibitor of kidney-type glutaminase: a withanolide from Physalis pubescens with potent anti-tumor activity
title_short A natural inhibitor of kidney-type glutaminase: a withanolide from Physalis pubescens with potent anti-tumor activity
title_sort natural inhibitor of kidney-type glutaminase: a withanolide from physalis pubescens with potent anti-tumor activity
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768343/
https://www.ncbi.nlm.nih.gov/pubmed/29371926
http://dx.doi.org/10.18632/oncotarget.23058
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