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Title: Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia

Abstract

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.

Authors:
ORCiD logo [1];  [2];  [1];  [1];  [1]; ORCiD logo [2];  [1];  [2];  [2];  [2];  [2];  [2];  [2];  [1];  [1];  [1];  [1]; ORCiD logo [2];  [2];  [1] more »;  [3]; ORCiD logo [4]; ORCiD logo [1] « less
  1. Nankai Univ., Tianjin (China)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Southern Medical Univ., Guangzhou (China)
  4. Nankai Univ., Tianjin (China); Georgia State Univ., Atlanta, GA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC); Univ. of California, Oakland, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1543635
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 61; Journal Issue: 9; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Pharmacology & Pharmacy

Citation Formats

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, and Chen, Yue. Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia. United States: N. p., 2018. Web. doi:10.1021/acs.jmedchem.8b00241.
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. United States. doi:10.1021/acs.jmedchem.8b00241.
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, and Chen, Yue. Wed . "Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia". United States. doi:10.1021/acs.jmedchem.8b00241. https://www.osti.gov/servlets/purl/1543635.
@article{osti_1543635,
title = {Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia},
author = {Li, Jing and Li, Shanshan and Guo, Jianshuang and Li, Qiuying and Long, Jing and Ma, Cheng and Ding, Yahui and Yan, Chunli and Li, Liangwei and Wu, Zhigang and Zhu, He and Li, Keqin Kathy and Wen, Liuqing and Zhang, Quan and Xue, Qingqing and Zhao, Caili and Liu, Ning and Ivanov, Ivaylo and Luo, Ming and Xi, Rimo and Long, Haibo and Wang, Peng George and Chen, Yue},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.8b00241},
journal = {Journal of Medicinal Chemistry},
number = 9,
volume = 61,
place = {United States},
year = {2018},
month = {4}
}

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Works referencing / citing this record:

The anti-tumor growth effect of a novel agent DMAMCL in rhabdomyosarcoma in vitro and in vivo
journal, March 2019

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