Nitric oxide induces promyelocytic cell growth arrest and apoptosis through deactivation of Akt pathway.
It is NO that mediates the inhibitory effect of IFN-gamma, MIP-1alpha and TNFalpha on hematopoiesis. However, the mechanism for NO effect on the hematopoietic system is likely to not clear. In the current work, we demonstrates that NO can directly suppress the colony formation of granulocyte/macrophage in vitro. Using a granulocyte/macrophage progenitor (GMP) model, HL-60 cell line, we show that NO inhibits the proliferation of HL-60 cells by inducing G0/G1 arrest and apoptosis in a dose- and time-dependent manner. Exposure of HL-60 cells to 1mM SNP for 2-48h results in marked decrease in Akt activation and Bad phosphorylation. Constitutively active Akt overexpression reduces NO-induced apoptosis and cell cycle arrest in HL-60 cells. A further investigation on apoptosis related protein shows that NO induces Bid cleavage and Bax expression but down-regulates the expression of Bcl-2 and Bcl-xL. We also demonstrate here that G0/G1 arrest is resulted from NO-induced disruption of cell cycle balance, which is mediated by up-regulation of p21(waf/cip1), p27(kip1) and down-regulation of cyclin D1, cyclin E. In brief, NO-induced apoptosis and G0/G1 arrest is mediated through regulation of apoptosis and cell cycle related protein, which may depend on Akt deactivation by NO, ultimately led to its inhibitory effect on hematopoiesis.
Wang
Xiaojian
X
Institute of Immunology, Tsinghua University School of Medicine, Beijing 100084, PR China. wangxiaojian@cad.zju.edu.cn
Sun
Hongying
H
Li
Chaolong
C
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D020030:Nitric Oxide Donors; D019253:Proto-Oncogene Proteins c-bcl-2; D009599:Nitroprusside; D009569:Nitric Oxide; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases