Critical role of extracellular signal-regulated kinase (ERK) phosphorylation in novel vitamin K analog-induced cell death.
In the present study, we show that 2-(2-hydroxyethylsulfaryl)-3-methyl-1,4-naphthoquinone, or CPD 5, is a potent growth inhibitor for pancreas cancer cell lines (ID(50): 21.4 +/- 3.8, 31.8 +/- 2.7 and 55.2 +/- 4.5 microM for MiaPaCa, Panc-1 and BxPc3, respectively). It induced protein tyrosine phosphor-ylation of hepatocyte growth factor (HGF) receptor (c-Met) or epidermal growth factor receptor (EGFR), which increased progressively to a maximum level at 30 min in Panc-1 cells. The receptor phosphorylation by CPD 5 was indicated to be functional, since these receptors were found to bind with Grb2 or SOS1 protein. CPD 5 was also suggested to induce phosphorylation of external signal-regulated kinase (ERK). EGF induced cell proliferation through ERK phosphorylation, since U0126, which is an inhibitor of ERK phosphorylation, abrogated the increase of cyclin D1 by EGF. HGF increased the amount of p27 protein, suggesting that it is associated with cell differentiation. By contrast, U0126 reduced CPD 5-induced cell death. On two-dimensional electrophoresis, we found an extra type of phospho-ERK, and this was completely and selectively abolished by U0126. These results suggest that ERK phosphorylation, especially the extra spot on two-dimensional gel, is critically associated with CPD 5-mediated cell death.
Osada
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Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA. CYP05471@nifty.ne.jp
Carr
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D000970:Antineoplastic Agents / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009124:Muscle Proteins; D009285:Naphthoquinones / Q000633:toxicity*; D010190:Pancreatic Neoplasms; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014812:Vitamin K / Q000031:analogs & derivatives* / Q000633:toxicity*
C420442:2-(2-hydroxyethylsulfaryl)-3-methyl-1,4-naphthoquinone; D000970:Antineoplastic Agents; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009285:Naphthoquinones; C058992:Tagln protein, mouse; D014812:Vitamin K; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020928:Mitogen-Activated Protein Kinases