title: Down-regulation of superoxide dismutase 1 by PMA is involved in cell fate determination and mediated via protein kinase D2 in myeloid leukemia cells.
abstract: Myeloid leukemia cells maintain a high intracellular ROS level and use redox signals for survival. The metabolism of ROS also affects cell fate, including cell death and differentiation. Superoxide dismutases (SODs) are major antioxidant enzymes that have high levels of expression in myeloid leukemia cells. However, the role of SODs in the regulation of myeloid leukemia cells' biological function is still unclear. To investigate the function of SODs in myeloid leukemia cell death and differentiation, we used myeloid leukemia cell lines K562, MEG-01, TF-1, and HEL cells for this study. We found that PMA-induced megakaryocytic differentiation in myeloid leukemia cells is accompanied by cell death and SOD1 down-regulation, while SOD2 expression is not affected. The role of SOD1 is verified when ATN-224, a SOD1 specific inhibitor, inhibits cell proliferation and promotes cell death in myeloid leukemia cells without PMA treatment. Moreover, inhibition or silencing of SODs further increases cell death and decreases polyploidization induced by PMA while they were partially reversed by SOD1 overexpression. Thus, SOD1 expression is required for myeloid leukemia cell fate determination. In addition, the knockdown of PKD2 reduces cell death and promotes polyploidization induced by PMA. PMA/PKD2-mediated necrosis via PARP cleavage involves both SOD1-dependent and -independent pathways. Finally, ATN-224 enhanced the inhibition of cell proliferation by Ara-C. Taken together, the results demonstrate that SOD1 regulates cell death and differentiation in myeloid leukemia cells. ATN-224 may be beneficial for myeloid leukemia therapy.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Electronic address: vincent@mail.ncku.edu.tw.
authors.forename: Wai-Ming
authors.initials: WM
authors.lastname: Kan
mesh_terms: D002273:Carcinogens / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008982:Molybdenum / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D000091283:Protein Kinase D2; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D002273:Carcinogens; D009363:Neoplasm Proteins; D000091283:Protein Kinase D2; C000606290:SOD1 protein, human; D008982:Molybdenum; C020809:tetrathiomolybdate; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; D013755:Tetradecanoylphorbol Acetate
keywords: ATN-224; Myeloid leukemia; Protein kinase D2 (PKD2); Reactive oxygen species (ROS); Superoxide dismutase 1 (SOD1)