title: Indirubin-3'-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK.
abstract: Indirubin-3'-monoxime is a derivative of the bis-indole alkaloid indirubin, an active ingredient of a traditional Chinese medical preparation that exhibits anti-inflammatory and anti-leukemic activities. Indirubin-3'-monoxime is mainly recognized as an inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3. It inhibits proliferation of cultured cells, mainly through arresting the cells in the G1/S or G2/M phase of the cell cycle. Here, we report that indirubin-3'-monoxime is able to inhibit proliferation of NIH/3T3 cells by specifically inhibiting autophosphorylation of fibroblast growth factor receptor 1 (FGFR1), blocking in this way the receptor-mediated cell signaling. Indirubin-3'-monoxime inhibits the activity of FGFR1 at a concentration lower than that required for inhibition of phosphorylation of CDK2 and retinoblastoma protein and cell proliferation stimulated by fetal calf serum. The ability of indirubin-3'-monoxime to inhibit FGFR1 signaling was similar to that of the FGFR1 inhibitor SU5402. In addition, we found that indirubin-3'-monoxime activates long-term p38 mitogen-activated protein kinase activity, which stimulates extracellular signal-regulated kinase 1/2 in a way unrelated to the activity of FGFR1. Furthermore, we show that indirubin-3'-monoxime can inhibit proliferation of the myeloid leukemia cell line KG-1a through inhibition of the activity of the FGFR1 tyrosine kinase. The data presented here demonstrate previously unknown activities of indirubin-3'-monoxime that may have clinical implications.
authors.affiliation: Department of Biochemistry, Institute for Cancer Research at The National Hospital - The Norwegian Radium Hospital, University of Oslo, Oslo, Norway.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhen
authors.forename: V
authors.initials: V
authors.lastname: Sørensen
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
authors.forename: Z
authors.initials: Z
authors.lastname: Suo
authors.forename: A
authors.initials: A
authors.lastname: Wiedłocha
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D041681:NIH 3T3 Cells / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D010766:Phosphorylation; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D007211:Indoles; D010091:Oximes; D016160:Retinoblastoma Protein; C474021:indirubin-3'-monoxime; D016220:Fibroblast Growth Factor 1; C512478:EGFR protein, human; D066246:ErbB Receptors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051357:Cyclin-Dependent Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases