Xanthatin inhibits STAT3 and NF-κB signalling by covalently binding to JAK and IKK kinases

J Cell Mol Med. 2019 Jun;23(6):4301-4312. doi: 10.1111/jcmm.14322. Epub 2019 Apr 16.

Abstract

Aberrant activation of the signal transducer and activator of transcription 3 (STAT3) and the nuclear factor-κB (NF-κB) signalling pathways is associated with the development of cancer and inflammatory diseases. JAKs and IKKs are the key regulators in the STAT3 and NF-κB signalling respectively. Therefore, the two families of kinases have been the major targets for developing drugs to regulate the two signalling pathways. Here, we report a natural compound xanthatin from the traditional Chinese medicinal herb Xanthium L. as a potent inhibitor of both STAT3 and NF-κB signalling pathways. Our data demonstrated that xanthatin was a covalent inhibitor and its activities depended on its α-methylene-γ-butyrolactone group. It preferentially interacted with the Cys243 of JAK2 and the Cys412 and Cys464 of IKKβ to inactivate their activities. In doing so, xanthatin preferentially inhibited the growth of cancer cell lines that have constitutively activated STAT3 and p65. These data suggest that xanthatin may be a promising anticancer and anti-inflammation drug candidate.

Keywords: IKK inhibitor; JAK inhibitor; covalent interaction; natural compound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Furans / chemistry
  • Furans / pharmacology*
  • Humans
  • I-kappa B Kinase / metabolism*
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Janus Kinases / metabolism*
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • NF-kappa B / antagonists & inhibitors*
  • Phosphorylation
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • Signal Transduction
  • Tumor Cells, Cultured

Substances

  • Furans
  • NF-kappa B
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • xanthatin
  • Janus Kinases
  • I-kappa B Kinase