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.

Abstract

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 PPARgamma 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.

• Authors: Huawei Zeng, Min Wu, James H Botnen
• Journal: The Journal of nutrition (J Nutr) Vol. 139 Issue 9 Pg. 1613-8 (Sep 2009) ISSN: 1541-6100 [Electronic] United States
• PMID: 19625696 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• DNA-Binding Proteins
• MYCBP protein, human
• Organoselenium Compounds
• RNA, Messenger
• Transcription Factors
• methaneselenol
• Methionine
• Mitogen-Activated Protein Kinase 1
• Lyases
• Selenium
• Methanol

Topics

• Antineoplastic Agents (metabolism, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• DNA-Binding Proteins (antagonists & inhibitors, genetics)
• Fibrosarcoma (drug therapy, genetics, metabolism)
• G1 Phase (drug effects)
• Gene Expression
• Humans
• Lyases (metabolism)
• Methanol (analogs & derivatives, pharmacology)
• Methionine (metabolism, pharmacology)
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors)
• Organoselenium Compounds (pharmacology)
• RNA, Messenger (metabolism)
• Selenium (metabolism, pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• Transcription Factors (antagonists & inhibitors, genetics)