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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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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. |
format | Online Article Text |
id | pubmed-5768343 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
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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