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

Megumi Funakoshi-Tago, Tatsuaki Nagata, Kenji Tago, Masaki Tsukada, Kazuyuki Tanaka, Shigeo Nakamura, Tadahiko Mashino, Tadashi Kasahara

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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, C60-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.

Original languageEnglish
Pages (from-to)2024-2034
Number of pages11
JournalCellular Signalling
Volume24
Issue number11
DOIs
Publication statusPublished - 2012 Nov 1

Keywords

  • Apoptosis
  • Apoptosis signal-regulating kinase 1 (ASK1)
  • C-Jun N-terminal kinase (JNK)
  • Fullerene
  • JAK2 V617F mutation
  • Myeloproliferative neoplasms (MPNs)

ASJC Scopus subject areas

  • Cell Biology

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