A novel NF-kappaB inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors.
Constitutive phosphorylation of c-kit tyrosine kinase is the major cause of factor-independent proliferation of mast cells. Recently available tyrosine kinase inhibitors have shown marked activity against mast cell lines that carry wild-type c-kit, and some, but not others, carry mutant c-kit. Here we clearly demonstrated that a novel NF-kappaB inhibitor, IMD-0354, restrained factor-independent proliferation of mast cells with c-kit mutations but not of normal mast cells. In HMC-1 cells with the Asp816Val and Val560Gly mutations, we found that NF-kappaB was constitutively activated without exogenous stimulation. When the DNA-binding activity of NF-kappaB was inhibited by treatment with IMD-0354, cell proliferation was completely suppressed. We detected the expression of cyclin D2, D3, and E in HMC-1 cells and observed that cyclin D3 expression was dramatically decreased by treatment with IMD-0354. Abolishing protein kinase C or phosphatidylinositol 3 kinase pathways also inhibited NF-kappaB translocation to the nucleus, indicating the involvement of these signaling cascades in NF-kappaB activation in HMC-1 cells. Our findings indicated that autophosphorylated c-kit receptors induced NF-kappaB activation, resulting in the up-regulation of cyclin D3 expression and cell cycle progression. The observations from the current study suggest a therapeutic potential, in systemic mastocytosis, for compounds that interfere with NF-kappaB signaling.
Tanaka
Akane
A
Laboratory of Molecular Pathology and Therapeutics, Division of Animal Life Science, Graduate School, Institute of Symbiotic Science and Technology, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan.
Konno
Masayo
M
Muto
Susumu
S
Kambe
Naotomo
N
Morii
Eiichi
E
Nakahata
Tatsutoshi
T
Itai
Akiko
A
Matsuda
Hiroshi
H
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D019943:Amino Acid Substitution; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D016213:Cyclins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017354:Point Mutation; D011493:Protein Kinase C / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
D001549:Benzamides; D016213:Cyclins; D016328:NF-kappa B; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D011493:Protein Kinase C