QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Online Supplemental Material All Versions of this Article: 139/9/1613    most recent jn.109.110320v1 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zeng, H. Articles by Botnen, J. H. Search for Related Content PubMed PubMed Citation Articles by Zeng, H. Articles by Botnen, J. H.

---

Biochemical, Molecular, and Genetic Mechanisms

Methylselenol, a Selenium Metabolite, Induces Cell Cycle Arrest in G1 Phase and Apoptosis via the Extracellular-Regulated Kinase 1/2 Pathway and Other Cancer Signaling Genes^1–3,

⁴ USDA, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202-9034 and ⁵ Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, ND 58202

Methylselenol has been hypothesized to be a critical selenium (Se) metabolite for anticancer activity in vivo, and our previous study demonstrated that submicromolar methylselenol generated by incubating methionase with seleno-L-methionine inhibits the migration and invasive potential of HT1080 tumor cells. However, little is known about the association between cancer signal pathways and methylselenol's inhibition of tumor cell invasion. In this study, we demonstrated that methylselenol exposure inhibited cell growth and we used a cancer signal pathway-specific array containing 15 different signal transduction pathways involved in oncogenesis to study the effect of methylselenol on cellular signaling. Using real-time RT-PCR, we confirmed that cellular mRNA levels of cyclin-dependent kinase inhibitor 1C (CDKN1C), heme oxygenase 1, platelet/endothelial cell adhesion molecule, and PPAR genes were upregulated to 2.8- to 5.7-fold of the control. BCL2-related protein A1, hedgehog interacting protein, and p53 target zinc finger protein genes were downregulated to 26–52% of the control, because of methylselenol exposure. These genes are directly related to the regulation of cell cycle and apoptosis. Methylselenol increased apoptotic cells up to 3.4-fold of the control and inhibited the extracellular-regulated kinase 1/2 (ERK1/2) signaling and cellular myelocytomatosis oncogene (c-Myc) expression. Taken together, our studies identify 7 novel methylselenol responsive genes and demonstrate that methylselenol inhibits ERK1/2 pathway activation and c-Myc expression. The regulation of these genes is likely to play a key role in G1 cell cycle arrest and apoptosis, which may contribute to the inhibition of tumor cell invasion.

^* To whom correspondence should be addressed. E-mail: huawei.zeng{at}ars.usda.gov.

Manuscript received 18 May 2009. Initial review completed 4 June 2009. Revision accepted 2 July 2009.

Published online 22 July 2009.

This article has been cited by other articles:

				Y. Ma, L. Chen, G. M. Wright, S. R. Pillai, S. P. Chellappan, and W. D. Cress CDKN1C Negatively Regulates RNA Polymerase II C-terminal Domain Phosphorylation in an E2F1-dependent Manner J. Biol. Chem., March 26, 2010; 285(13): 9813 - 9822. [Abstract] [Full Text] [PDF]