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Molecules 2018, 23(6), 1478; https://doi.org/10.3390/molecules23061478

Parthenolide Inhibits STAT3 Signaling by Covalently Targeting Janus Kinases

1
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2
University of Chinese Academy of Sciences, Beijing 100049, China
3
Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
4
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
5
The Chemical Proteomics Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
*
Author to whom correspondence should be addressed.
Received: 21 May 2018 / Revised: 7 June 2018 / Accepted: 13 June 2018 / Published: 19 June 2018
(This article belongs to the Section Chemical Biology)
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Abstract

Aberrant activations of the STAT3 (signal transducer and activator of transcription 3) signaling pathway are associated with cancer and inflammatory diseases. Three of the four Janus kinases, JAK1, JAK2, and Tyk2, are the major upstream kinases of STAT3 in responses to cytokine stimulations. Among them, JAK2 is the key kinase in the IL-6-induced STAT3 phosphorylation. Here we report the mechanisms of a natural compound parthenolide from the medicinal herb Feverfew in regulating the JAK/STAT3 signaling. We found that parthenolide was a potent inhibitor of JAKs. It covalently modified the Cys178, Cys243, Cys335, and Cys480 of JAK2 and suppressed its kinase activity. It also interacted with other JAKs in a similar fashion. The binding of parthenolide to JAKs was selective. It preferentially bound to the JAKs, but not to the abundant proteins, such as tubulin and actin. Parthenolide also induced reactive oxygen species (ROS), but the increased ROS did not seem to contribute to the inhibition of JAK/STAT3 signaling. Furthermore, parthenolide inhibited the IL-6-induced cancer cell migration and preferentially inhibited the growth of cancer cells that had constitutively activated STAT3. Our study suggests a novel strategy to inactivate JAKs and provides a promising anti-inflammation and anticancer drug candidate. View Full-Text
Keywords: parthenolide; covalent inhibitor; cell death; JAK/STAT3 signaling parthenolide; covalent inhibitor; cell death; JAK/STAT3 signaling
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Liu, M.; Xiao, C.; Sun, M.; Tan, M.; Hu, L.; Yu, Q. Parthenolide Inhibits STAT3 Signaling by Covalently Targeting Janus Kinases. Molecules 2018, 23, 1478.

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