The induction of G2/M cell-cycle arrest and apoptosis by cucurbitacin E is associated with increased phosphorylation of eIF2alpha in leukemia cells.
The antiproliferative and apoptotic effects of cucurbitacin E, a natural product isolated from Cucurbitaceae, were determined in human leukemia HL-60 cells. Cucurbitacin E at low concentrations (3-50 nmol/l) inhibited the growth of HL-60 cells, which was associated with G2/M cell-cycle arrest, decrease in the levels of cyclin-dependent kinase1, and increase in the levels of p21. Cucurbitacin E at high concentrations (1-10 mol/l) induced apoptosis of HL-60 cells and activation of caspase-3, caspase-8, and caspase-9. Jurkat leukemia cells with or without caspase-8 expression were nearly equally sensitive to cucurbitacin E-induced apoptosis. Cucurbitacin E did not increase the levels of reactive oxygen species and antioxidants, N-acetylcysteine and catalase, did not block cucurbitacin E-induced apoptosis. Cucurbitacin E decreased the levels of the antiapoptotic proteins XIAP, survivin, and Mcl-1, but increased the level of the proapoptotic protein, Bax. The levels of phosphorylated eukaryotic translation initiation factor 2 subunit (eIF2) were induced in cells undergoing both apoptosis and cell-cycle arrest. As phosphorylated eIF2 is an inhibitor of protein translation initiation, our data suggest that cucurbitacin E induces cell growth arrest and apoptosis through the induction of eIF2 phosphorylation, which leads to the inhibition of cyclin-dependent kinase 1, Mcl-1, survivin, and/or XIAP protein synthesis and that cucurbitacin E induces apoptosis mainly through a mitochondrial-mediated pathway.
Li
Yanchun
Y
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China.
Wang
Rui
R
Ma
Enlong
E
Deng
Yihui
Y
Wang
Xiaolong
X
Xiao
Jinfang
J
Jing
Yongkui
Y
D000111:Acetylcysteine / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000187:drug effects / Q000378:metabolism*; D016195:G2 Phase / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077022:Survivin; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D015852:Eukaryotic Initiation Factor-2; D006131:Growth Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D000077022:Survivin; D014315:Triterpenes; D051636:X-Linked Inhibitor of Apoptosis Protein; D002374:Catalase; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; C102326:cucurbitacin E; D000111:Acetylcysteine