Hemangiopoietin inhibits apoptosis of MO7e leukemia cells through phosphatidylinositol 3-kinase-AKT pathway.
Hemangiopoietin (HAPO) is a growth factor that significantly stimulates proliferation and survival of the primitive cells of hematopoietic and endothelial lineages. To determine the mechanism of action of HAPO, the anti-apoptotic activity and signal transduction pathway of HAPO were investigated using a factor-dependent leukemia cell line, the MO7e cells. Recombinant human HAPO (rhHAPO) was produced in Escherichia coli and purified by a series of column chromatography with a purity of more than 95%. rhHAPO significantly supported the survival of MO7e cells after deprivation of granulocyte-macrophage colony stimulating factor and activated phosphatidylinositol 3-kinase (PI3K). When the MO7e cells were treated with two specific inhibitors to PI3K (LY294002 or wortmannin), a significant loss of cell viability with evidence of apoptosis was observed. Moreover, the protein kinase B (Akt), one of the downstream effectors of PI3K-dependent survival signaling, was activated in HAPO-stimulated MO7e cells. Phosphorylation of Akt at serine 473 and its downstream molecular Bad at serine 136 was induced by HAPO, but was blocked by two PI3K inhibitors, LY294002 and wortmannin. In addition, HAPO inhibited caspase-3 activities and poly(ADP-ribose) polymerase degradation. Such an effect of HAPO was also significantly blocked by either LY294002 or wortmannin. These results indicate that HAPO protects MO7e cells from apoptotic death through a PI3K-Akt pathway.
Zhan
Mei
M
State key Laboratory of Experimental Hematology, Institute of Hematology, National Research Center for Stem Cell Engineering and Technology, Chinese Academy of Medical Sciences and Peking Union of Medical College, Tianjin, China.
Han
Zhong Chao
ZC
D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency; D006133:Growth Substances / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D015398:Signal Transduction; D000077191:Wortmannin; D051025:bcl-Associated Death Protein
D000730:Androstadienes; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D002867:Chromones; D004791:Enzyme Inhibitors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances; D009025:Morpholines; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D011505:Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D015682:Retroviridae Proteins, Oncogenic; D000077191:Wortmannin; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one