Selenomethionine induces sustained ERK phosphorylation leading to cell-cycle arrest in human colon cancer cells.
Selenomethionine (SeMet) is being tested alone and in combination with other agents in cancer chemoprevention trials. However, the molecular targets and the signaling mechanism underlying the anticancer effect of this compound are not completely clear. Here, we provide evidence that SeMet can induce cell-growth arrest and that the growth inhibition is associated with S-G2/M cell-cycle arrest. Coincidentally with the cell-cycle arrest, we observed a striking increase in cyclin B as well as phosphorylation of the cyclin-dependent kinase Cdc2. Since activation of the mitogen-activated protein kinase (MAPK) cascade has been associated with cell-cycle arrest and growth inhibition, we evaluated the activation of extracellular signal-regulated kinase (ERK). We found that SeMet induced phosphorylation of the MAPK ERK in a dose-dependent manner. We also demonstrate phosphorylation of ribosomal S6 kinase (p90RSK) by SeMet. Additionally, we show phosphorylation of histone H3 in a concentration-dependent manner. Furthermore, the phosphorylation of p90RSK and histone H3 were both antagonized by the MEK inhibitor U0126, implying that SeMet-induced phosphorylation of p90RSK and histone H3 are at least in part ERK pathway dependent. Based on these results, we propose that SeMet induced growth arrest and phosphorylation of histone H3 are mediated by persistent ERK and p90RSK activation. These new data provide valuable insights into the biological effects of SeMet at clinically relevant concentrations.
Goulet
Anne-Christine
AC
Department of Pathology, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
Chigbrow
Marianne
M
Frisk
Peter
P
Nelson
Mark A
MA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D019926:Cyclin B / Q000187:drug effects / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects*; D045325:HCT116 Cells; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000187:drug effects / Q000378:metabolism; D012645:Selenomethionine / Q000494:pharmacology*
D000970:Antineoplastic Agents; D019926:Cyclin B; D006657:Histones; D012645:Selenomethionine; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases