title: The synergistic repressive effect of NF-κB and JNK inhibitor on the clonogenic capacity of Jurkat leukemia cells.
abstract: Deregulation of Nuclear Transcription Factor-κB (NF-κB) and Jun N-terminal kinase (JNK) signaling is commonly detected in leukemia, suggesting an important role for these two signaling pathways in the pathogenesis of leukemia. In this study, using Jurkat cells, an acute T-lymphoblastic leukemia (T-ALL) cell line, we evaluated the effects of an NF-κB inhibitor and a JNK inhibitor individually and in combination on the proliferation, survival and clonogenic capacity of leukemic cells. We found that leukemic stem/progenitor cells (LSPCs) were more sensitive to NF-κB inhibitor treatment than were healthy hematopoietic stem/progenitor cells (HSPCs), as shown by a reduction in the clonogenic capacity of the former. Inactivation of NF-κB leads to the activation of JNK signaling in both leukemic cells and healthy HSPCs. Interestingly, JNK inhibitor treatment enhanced the repressive effects of NF-κB inhibitor on LSPCs but prevented such repression in HSPCs. Our data suggest that JNK signaling stimulates proliferation/survival in LSPCs but is a death signal in HSPCs. The combination of NF-κB inhibitor and JNK inhibitor might provide a better treatment for T-ALL leukemia by synergistically killing LSPCs while simultaneously preventing the death of normal HPCs.
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.
authors.forename: Xinli
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center and Departments of Pathology and Molecular/Cellular Physiology, Loyola University Chicago, Maywood, IL 60153, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Volk
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center and Departments of Pathology and Molecular/Cellular Physiology, Loyola University Chicago, Maywood, IL 60153, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Breslin
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center and Departments of Pathology and Molecular/Cellular Physiology, Loyola University Chicago, Maywood, IL 60153, United States of America.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: College of Life Science and Biopharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000873:Anthracenes / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000873:Anthracenes; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; C432165:pyrazolanthrone