3-Deoxy-2β,16-dihydroxynagilactone E, a natural compound from Podocarpus nagi, preferentially inhibits JAK2/STAT3 signaling by allosterically interacting with the regulatory domain of JAK2 and induces apoptosis of cancer cells

Abstract

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, especially the JAK2/STAT3 pathway, play vital roles in the development of many malignancies. Overactivation of STAT3 promotes cancer cell survival and proliferation. Therefore, the JAK2/STAT3-signaling pathway has been considered a promising target for cancer therapy. In this study, we identified a natural compound 3-deoxy-2β,16-dihydroxynagilactone E (B6) from the traditional Chinese medicinal plant Podocarpus nagi as a potent inhibitor of STAT3 signaling. B6 preferentially inhibited the phosphorylation of STAT3 by interacting with and inactivating JAK2, the main upstream kinase of STAT3. B6 dose-dependently inhibited IL-6-induced STAT3 signaling with an IC50 of 0.2 μM. In contrast to other JAK2 inhibitors, B6 did not interact with the catalytic domain but instead with the FERM-SH2 domain of JAK2. This interaction was JAK-specific since B6 had little effect on other tyrosine kinases. Furthermore, B6 potently inhibited the growth and induced apoptosis of MDA-MB-231 and MDA-MB-468 breast cancer cells with overactivated STAT3. Taken together, our study uncovers a novel compound and a novel mechanism for the regulation of JAK2 and offers a new therapeutic approach for the treatment of cancers with overactivated JAK2/STAT3.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant 81673465 to QY). We thank Xin-yuan Fu (National University of Singapore) for providing HepG2/STAT3 and HepG2/STAT1 cells. We also thank Hui Wang (Shanghai Institute of Materia Medica) for help with the amino acid sequence analysis.

Author information

QY and HS conceived and designed the experiments. HS wrote the manuscript, performed experiments, and analyzed the data. SY and YY synthesized the compound 3-deoxy-2β,16-dihydroxynagilactone E (B6).

Correspondence to Qiang Yu.

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The authors declare no competing interests.

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Keywords

  • JAK/STAT
  • 3-deoxy-2β,16-dihydroxynagilactone E
  • tyrosine kinase inhibitor
  • allosteric inhibitor
  • cancer

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