title: Fullerene derivative prevents cellular transformation induced by JAK2 V617F mutant through inhibiting c-Jun N-terminal kinase pathway.
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, 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.
authors: Department of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan. tago-mg@pha.keio.ac.jp
authors: Megumi
authors: M
authors: Funakoshi-Tago
authors: Tatsuaki
authors: T
authors: Nagata
authors: Kenji
authors: K
authors: Tago
authors: Masaki
authors: M
authors: Tsukada
authors: Kazuyuki
authors: K
authors: Tanaka
authors: Shigeo
authors: S
authors: Nakamura
authors: Tadahiko
authors: T
authors: Mashino
authors: Tadashi
authors: T
authors: Kasahara
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D037741:Fullerenes / Q000737:chemistry / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000873:Anthracenes; D037741:Fullerenes; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; C432165:pyrazolanthrone; D053614:Janus Kinase 2; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7