Fullerene derivative prevents cellular transformation induced by JAK2 V617F mutant through inhibiting c-Jun N-terminal kinase pathway

Cell Signal. 2012 Nov;24(11):2024-34. doi: 10.1016/j.cellsig.2012.06.014. Epub 2012 Jun 30.


The constitutively activated mutation (V617F) of tyrosine kinase Janus kinase 2 (JAK2) is found in the majority of patients with myeloproliferative neoplasms (MPNs). The development of a novel chemical compound to suppress JAK2 V617F mutant-induced onset of MPNs and clarification of the signaling cascade downstream of JAK2 V617F mutant will provide clues to treat MPNs. Here we found that a water-soluble pyrrolidinium fullerene derivative, C(60)-bis (N, N-dimethylpyrrolidinium iodide), markedly induced apoptosis of JAK2 V617F mutant-induced transformed cells through a novel mechanism, inhibiting c-Jun N-terminal kinase (JNK) activation pathway but not generation of reactive oxygen species (ROS). Pyrrolidinium fullerene derivative significantly reduced the protein expression level of apoptosis signal-regulating kinase 1 (ASK1), one of the mitogen-activated protein kinase kinase kinases (MAPKKK), resulting in the inhibition of upstream molecules of JNK, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7). Strikingly, the knockdown of ASK1 enhanced the sensitivity to pyrrolidinium fullerene derivative-induced apoptosis, and the treatment with a JNK inhibitor, SP600125, also induced apoptosis of the transformed cells by JAK2 V617F mutant. Furthermore, administration of both SP600125 and pyrrolidinium fullerene derivative markedly inhibited JAK2 V617F mutant-induced tumorigenesis in nude mice. Taking these findings together, JAK2 V617F mutant-induced JNK signaling pathway is an attractive target for MPN therapy, and pyrrolidinium fullerene derivative is now considered a candidate potent drug for MPNs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Anthracenes / pharmacology
  • Apoptosis / drug effects
  • Cell Line
  • Cell Transformation, Neoplastic / drug effects*
  • Fullerenes / chemistry
  • Fullerenes / pharmacology*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism*
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Kinase 7 / metabolism
  • MAP Kinase Kinase Kinase 5 / antagonists & inhibitors
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Nude
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • Transcription Factor AP-1 / metabolism


  • Anthracenes
  • Fullerenes
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Transcription Factor AP-1
  • pyrazolanthrone
  • Janus Kinase 2
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases
  • MAP Kinase Kinase 4
  • MAP Kinase Kinase 7