title: Induction of apoptosis in BCR/ABL+ cells by histone deacetylase inhibitors involves reciprocal effects on the RAF/MEK/ERK and JNK pathways.
abstract: Signal transduction events regulating induction of apoptosis by the histone deacetylase inhibitors (HDIs) sodium butyrate (SB) and SAHA have been examined in Bcr/Abl+ human leukemia cells (K562, LAMA 84). Exposure of K562 cells to greater or less than 3.0 mM SB or 3.0 mM SAHA for 24-48 hr resulted in a marked induction of mitchondrial damage (e.g., cytochrome c release) and apoptosis, events associated with downregulation of Bcr/Abl and Raf-1, induction of p21CIP1, inactivation of MEK1/2, ERK1/2, and p70S6K, and a dramatic increase in JNK activation. HDI-mediated apoptosis was attenuated by pharmacologic JNK inhibitors and enhanced by the MEK1/2 inhibitor U0126 as well as by the JNK activator anisomycin. Interestingly, HDI-induced JNK activation was potentiated by pharmacologic MEK inhibition. Furthermore, HDI lethality was significantly diminished in cells ectopically expressing constitutively active MEK1, confirming a functional role for MEK/ERK inactivation in HDI-mediated apoptosis. Similar events were observed in Bcr/Abl+ LAMA 84 cells. Lastly, the free radical scavenger L-N-acetylcysteine (LNAC) attenuated HDI-mediated ROS generation, JNK activation, and apoptosis. Together, these findings support a model in which induction of apoptosis in Bcr/Abl+ cells by HDIs involves coordinate inactivation of the cytoprotective Raf/MEK/ERK pathway in conjunction with the ROS-dependent activation of JNK.
authors: Department of Medicine, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia USA.
authors: Chunrong
authors: C
authors: Yu
authors: Mark
authors: M
authors: Subler
authors: Mohamed
authors: M
authors: Rahmani
authors: Erin
authors: E
authors: Reese
authors: Geoffrey
authors: G
authors: Krystal
authors: Daniel
authors: D
authors: Conrad
authors: Paul
authors: P
authors: Dent
authors: Steven
authors: S
authors: Grant
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020014:K562 Cells / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D048670:MAP Kinase Kinase 4; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D045304:Cytochromes c; D016044:Fusion Proteins, bcr-abl; D019908:Proto-Oncogene Proteins c-raf; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases