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.
Highlights
The JAK/STAT (Janus kinase/signal transducer and activator of transcription) signaling pathways are major pathways for cytokine signaling and regulate important cellular events, such as hematopoiesis and immune development [1,2]
CYT387, BMS911543, or TG101348 were cross-persistent to ruxolitinib [21]. These findings suggest that more JAK2 inhibitors with different mechanisms are needed to improve efficacy
We found that PN directly inhibited JAK2 activity with an IC50 of 3.937 μmol/L (Figure 1F), demonstrating that PN inhibited the IL-6-induced STAT3 phosphorylation by directly inhibiting JAK2 kinase activity
Summary
The JAK/STAT (Janus kinase/signal transducer and activator of transcription) signaling pathways are major pathways for cytokine signaling and regulate important cellular events, such as hematopoiesis and immune development [1,2]. CYT387, BMS911543, or TG101348 were cross-persistent to ruxolitinib [21] These findings suggest that more JAK2 inhibitors with different mechanisms are needed to improve efficacy. In this regard, covalent inhibitors have their unique advantages over ATP-competitive kinase inhibitors, because they can irreversibly interact with their targets and prevent the reactivation of JAK-STAT signaling described above. Covalent inhibitors can dissociate drug pharmacodynamics from pharmacokinetics, resulting in desired drug efficacy with short systemic exposure to decrease drug interactions with off-targets. It can achieve prolonged effects, resulting in less-frequent drug dosing [22]. Our study provides a covalent strategy to develop a JAK inhibitor and suggests PN as a promising anti-inflammation and anticancer drug candidate
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