Selenomethionine induces sustained ERK phosphorylation leading to cell-cycle arrest in human colon cancer cells

Anne Christine Goulet, Marianne Chigbrow, Peter Frisk, Mark A Nelson

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)109-117
Number of pages9
JournalCarcinogenesis
Volume26
Issue number1
DOIs
StatePublished - Jan 2005

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Selenomethionine
Extracellular Signal-Regulated MAP Kinases
Cell Cycle Checkpoints
Colonic Neoplasms
Phosphorylation
Histones
Growth
Mitogen-Activated Protein Kinases
G2 Phase Cell Cycle Checkpoints
Ribosomal Protein S6 Kinases
Cyclin B
Cyclin-Dependent Kinases
Mitogen-Activated Protein Kinase Kinases
Chemoprevention

ASJC Scopus subject areas

  • Cancer Research

Cite this

Selenomethionine induces sustained ERK phosphorylation leading to cell-cycle arrest in human colon cancer cells. / Goulet, Anne Christine; Chigbrow, Marianne; Frisk, Peter; Nelson, Mark A.

In: Carcinogenesis, Vol. 26, No. 1, 01.2005, p. 109-117.

Research output: Contribution to journalArticle

Goulet, Anne Christine ; Chigbrow, Marianne ; Frisk, Peter ; Nelson, Mark A. / Selenomethionine induces sustained ERK phosphorylation leading to cell-cycle arrest in human colon cancer cells. In: Carcinogenesis. 2005 ; Vol. 26, No. 1. pp. 109-117.
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