|Wu, Min -|
Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 2, 2009
Publication Date: September 1, 2009
Repository URL: http://handle.nal.usda.gov/10113/35455
Citation: Zeng, H., Wu, M., Botnen, J.H. 2009. 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. Journal of Nutrition. 139:1613-1618. Interpretive Summary: Selenium is an essential trace element for humans and animals, and selenium intakes that are greater than the recommended daily allowance (RDA) appear to protect against certain types of cancers.In humans and animals, cell proliferation and death must be regulated to maintain tissue homeostasis, and it has been well documented that the control of cell cycle progression and apoptosis is directly related to numerous human diseases. Our previous study demonstrates 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 cancer signal pathway related to methylselenol’s inhibition of tumor cell invasion. Thus, the elucidation of the mechanisms by which selenium regulates the cell cycle and apoptosis can lead to a better understanding of the nature of selenium’s essentiality and its role in disease prevention. This article reviews the status of knowledge concerning the effect of selenium on cell cycle and apoptosis. The information will be useful information for scientists and health-care professionals who are interested in nutrition and cancer prevention.
Technical Abstract: Methylselenol has been hypothesized to be a critical selenium metabolite for anticancer activity in vivo, and our previous study demonstrates 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 cancer signal pathway related to methylselenol’s inhibition of tumor cell invasion. In this report, we demonstrated that methylselenol exposure inhibited cell growth, and we employed a cancer signal pathway specific array containing 15 different signal transduction pathways involved in oncogenesis to study the effect of methylselenol on cellular signaling. With the real time RT-PCR method, we confirmed that the mRNA levels of cell CDKN1C, HMOX1, PECAM1, PPARG genes were increased by 1.8 to 4.7 fold; BCL2A1, HHIP, WIG1 genes were down-regulated by 28.4 to 74.2% because of methylselenol exposure. These genes are directly related to the regulation of cell cycle and apoptosis. Subsequently, we showed that methylselenol exposure led to an increase in the G1 and G2 with a concomitant drop in S-phase in cell cycle progression. In addition, methylselenol increased apoptotic rate of tumor cells up to 2.4 fold, and inhibited the extracellular-regulated kinase 1/2 (ERK1/2) signaling and c-Myc expression. Taken together, our studies identify 7 novel methylselenol responsive genes, and suggest the regulation of these genes, ERK1/2 pathway inactivation and reduction of c-Myc expression by methylselenol play a key role in G1 cell cycle arrest and apoptosis, which may contribute to the inhibition of tumor cell invasion.