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Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia
[Image: see text] Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively acti...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949721/ https://www.ncbi.nlm.nih.gov/pubmed/29641204 http://dx.doi.org/10.1021/acs.jmedchem.8b00241 |
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author | Li, Jing Li, Shanshan Guo, Jianshuang Li, Qiuying Long, Jing Ma, Cheng Ding, Yahui Yan, Chunli Li, Liangwei Wu, Zhigang Zhu, He Li, Keqin Kathy Wen, Liuqing Zhang, Quan Xue, Qingqing Zhao, Caili Liu, Ning Ivanov, Ivaylo Luo, Ming Xi, Rimo Long, Haibo Wang, Peng George Chen, Yue |
author_facet | Li, Jing Li, Shanshan Guo, Jianshuang Li, Qiuying Long, Jing Ma, Cheng Ding, Yahui Yan, Chunli Li, Liangwei Wu, Zhigang Zhu, He Li, Keqin Kathy Wen, Liuqing Zhang, Quan Xue, Qingqing Zhao, Caili Liu, Ning Ivanov, Ivaylo Luo, Ming Xi, Rimo Long, Haibo Wang, Peng George Chen, Yue |
author_sort | Li, Jing |
collection | PubMed |
description | [Image: see text] Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents. |
format | Online Article Text |
id | pubmed-5949721 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-59497212018-05-15 Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia Li, Jing Li, Shanshan Guo, Jianshuang Li, Qiuying Long, Jing Ma, Cheng Ding, Yahui Yan, Chunli Li, Liangwei Wu, Zhigang Zhu, He Li, Keqin Kathy Wen, Liuqing Zhang, Quan Xue, Qingqing Zhao, Caili Liu, Ning Ivanov, Ivaylo Luo, Ming Xi, Rimo Long, Haibo Wang, Peng George Chen, Yue J Med Chem [Image: see text] Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents. American Chemical Society 2018-04-11 2018-05-10 /pmc/articles/PMC5949721/ /pubmed/29641204 http://dx.doi.org/10.1021/acs.jmedchem.8b00241 Text en Copyright © 2018 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Li, Jing Li, Shanshan Guo, Jianshuang Li, Qiuying Long, Jing Ma, Cheng Ding, Yahui Yan, Chunli Li, Liangwei Wu, Zhigang Zhu, He Li, Keqin Kathy Wen, Liuqing Zhang, Quan Xue, Qingqing Zhao, Caili Liu, Ning Ivanov, Ivaylo Luo, Ming Xi, Rimo Long, Haibo Wang, Peng George Chen, Yue Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia |
title | Natural Product
Micheliolide (MCL) Irreversibly Activates
Pyruvate Kinase M2 and Suppresses Leukemia |
title_full | Natural Product
Micheliolide (MCL) Irreversibly Activates
Pyruvate Kinase M2 and Suppresses Leukemia |
title_fullStr | Natural Product
Micheliolide (MCL) Irreversibly Activates
Pyruvate Kinase M2 and Suppresses Leukemia |
title_full_unstemmed | Natural Product
Micheliolide (MCL) Irreversibly Activates
Pyruvate Kinase M2 and Suppresses Leukemia |
title_short | Natural Product
Micheliolide (MCL) Irreversibly Activates
Pyruvate Kinase M2 and Suppresses Leukemia |
title_sort | natural product
micheliolide (mcl) irreversibly activates
pyruvate kinase m2 and suppresses leukemia |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949721/ https://www.ncbi.nlm.nih.gov/pubmed/29641204 http://dx.doi.org/10.1021/acs.jmedchem.8b00241 |
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