Carcinogenesis Advance Access published online on October 28, 2004
Carcinogenesis, doi:10.1093/carcin/bgh306
© 2004 by Oxford University Press
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1 Department of Pathology, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724
* To whom correspondence should be addressed. Selenomethionine 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 selenomethionine 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 A and 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 selenomethionine induced phosphorylation of the MAPK ERK in a dose-dependent manner. We also demonstrated phosphorylation of ribosomal S6 kinase (p90RSK) by selenomethionine. Additionally, we showed 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 selenomethionine induced phosphorylation of p90RSK and histone H3 are at least in part ERK pathway dependent. Based on these results, we propose that selenomethionine 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 selenomethionine at clinically relevant concentrations.
Revised September 16, 2004
Accepted October 1, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Selenomethionine induces sustained ERK phosphorylation leading to cell cycle arrest in human colon cancer cells
Mark A. Nelson, E-mail: mnelson{at}azcc.arizona.edu
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