2-D gel electrophoresis-based proteomic analysis reveals that ormeloxifen induces G0-G1 growth arrest and ERK-mediated apoptosis in chronic myeloid leukemia cells K562
| Autor: | Pooja Pal, Pradhyumna Kumar Singh, Madan L.B. Bhatt, Savita Lochab, Sabyasachi Sanyal, Jitendra Kumar Kanaujiya, Shashi B. Tripathi, Arun Kumar Trivedi |
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| Rok vydání: | 2011 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Proteomics MAPK/ERK pathway Clinical Biochemistry Apoptosis Polymerase Chain Reaction Resting Phase Cell Cycle Biochemistry Mass Spectrometry Proto-Oncogene Proteins c-myc Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases In Situ Nick-End Labeling medicine Humans Benzopyrans Electrophoresis Gel Two-Dimensional Phosphorylation Extracellular Signal-Regulated MAP Kinases Promoter Regions Genetic Molecular Biology Flavonoids Inhibitor of apoptosis domain biology Caspase 3 G1 Phase Myeloid leukemia medicine.disease Mitochondria DNA-Binding Proteins Leukemia Mitogen-activated protein kinase Cancer research biology.protein K562 Cells K562 cells Chronic myelogenous leukemia |
| Zdroj: | PROTEOMICS. 11:1517-1529 |
| ISSN: | 1615-9853 |
| Popis: | Ormeloxifen is a nonsteroidal selective estrogen receptor modulator (SERM) and has been shown to possess anticancer activities in breast and uterine cancer. Here, we show that ormeloxifen induces apoptosis in dose-dependent manner in a variety of leukemia cells, more strikingly in K562. 2-DE-gel electrophoresis of K562 cells induced with ormeloxifen showed that 57 and 30% of proteins belong to apoptosis and cell-cycle pathways, respectively. Our data demonstrate that ormeloxifen-induced apoptosis in K562 cells involves activation of extracellular signal-regulated kinases (ERKs) and subsequent cytochrome c release, leading to mitochondria-mediated caspase-3 activation. Ormeloxifen-induced apoptosis via ERK activation was drastically inhibited by prior treatment of K562 cells with ERK inhibitor PD98059. Ormeloxifen also inhibits proliferation of K562 cells by blocking them in G0-G1 phase by inhibiting c-myc promoter via ormeloxifen-induced MBP-1 (c-myc promoter-binding protein) and upregulation of p21 expression. We further show that ormeloxifen-induced apoptosis in K562 is translatable to mononuclear cells isolated from chronic myeloid leukemia (CML) patients. Thus, ormeloxifen induces apoptosis in K562 cells via phosphorylation of ERK and arrests them in G0-G1 phase by reciprocal regulation of p21 and c-myc. Therefore, inclusion of ormeloxifen in the therapy of chronic myeloid leukemia can be of potential utility. |
| Databáze: | OpenAIRE |
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