title: NF-κB suppresses ROS levels in BCR-ABL(+) cells to prevent activation of JNK and cell death.
abstract: Elevated levels of reactive oxygen species (ROS) are found in most oncogenically transformed cells and are proposed to promote cellular transformation through mechanisms such as inhibition of phosphatases. BCR-ABL, the oncoprotein associated with the majority of chronic myeloid leukemias (CMLs), induces accumulation of intracellular ROS, causing enhanced signaling downstream of PI3K. Previously we have shown that the transcription factor nuclear factor-kappa B (NF-κB) is activated by BCR-ABL expression and is required for BCR-ABL-mediated cellular transformation. Inhibition of IκB kinase (IKKβ) and NF-κB leads to cell death through an unknown mechanism. Here, we analyze the potential involvement of NF-κB in moderating BCR-ABL-induced ROS levels to protect from death. The data confirm that BCR-ABL promotes ROS and demonstrate that NF-κB prevents excessive levels. Inhibition of NF-κB leads to an increase in ROS levels and to cell death, which is at least partially controlled through ROS-induced c-Jun N-terminal kinase activity. The data demonstrate that one function for NF-κB in oncogenesis is the suppression of oncoprotein-induced ROS levels and that inhibition of NF-κB in some cancers, including CML, will increase ROS levels and promote cell death.
authors.affiliation: Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Stein
authors.forename: A S
authors.initials: AS
authors.lastname: Baldwin
mesh_terms: D000818:Animals; D017209:Apoptosis; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016313:Genes, abl / Q000502:physiology*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D052002:NF-kappa B p50 Subunit; D017382:Reactive Oxygen Species; C073701:Nfkb1 protein, mouse; D051550:I-kappa B Kinase; D048670:MAP Kinase Kinase 4