The role of superoxide dismutase 1 in myeloid leukemia

Abstract

Differentiation-inducing therapy is used to treat patients who have undifferentiated cancer such as leukemia During induction stimulation leukemia cell differentiation is always observed together with cell death Reactive oxygen species (ROS) metabolism is involved in myeloid leukemia cell proliferation death and differentiation Superoxide dismutases (SODs) are major antioxidant enzymes that are highly expressed in myeloid leukemia cells However the role of SODs in cell death and differentiation is still largely unknown In this study we used phorbol-12-myristate-13-acetate (PMA) to treat myeloid leukemia cell lines for the study We found that PMA-induced megakaryocytic differentiation in myeloid leukemia cells is accompanied with cell death and SOD1 down-regulation while SOD2 expression is not affected Moreover inhibition or silencing of SODs further increases cell death and decreases polyploidization induced by PMA that could be partially reversed by SOD1 overexpression Moreover PMA-attenuated SOD1 expression can be reversed by silencing of protein kinase D2 (PKD2) and protein kinase Cδ (PKCδ) Furthermore PKD2 inhibited polyploidization and PKCδ suppressed the expression of selective megakaryocyte (MK) surface marker CD41 and CD61 while both PKD2 and PKCδ silencing reduced the basal level of glycophorin A (GPA) in untreated myeloid leukemia cells These results indicate that both PKD2 and PKCδ participated in differentiation regulation N-acetylcysteine (NAC) and silencing of PKD2 or PKCδ also reversed the necrotic death signal including activation of cathepsin B and cleavage of poly (ADP-ribose) polymerase (PARP) induced by PMA The role of SOD1 is clarified when ATN-224 a SOD1 specific inhibitor inhibits cell proliferation and promotes cell death in myeloid leukemia cells without PMA treatment 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 Inhibition of SOD1 by inhibitor such as ATN-224 may be beneficial for myeloid leukemia therapy

Date of Award	2016 Jan 7
Original language	English
Supervisor	Wai-Ming Kan (Supervisor)