Induction of caspase-mediated apoptosis and cell-cycle G1 arrest by selenium metabolite methylselenol.

Abstract

Previous work based on mono-methyl selenium compounds that are putative precursors of methylselenol has strongly implicated this metabolite in the induction of caspase-mediated apoptosis of human prostate carcinoma and leukemia cells and G1 arrest in human vascular endothelial and cancer epithelial cells. To test the hypothesis that methylselenol itself is responsible for exerting these cellular effects, we examined the apoptotic action on DU145 human prostate cancer cells and the G1 arrest effect on the human umbilical vein endothelial cells (HUVECs) of methylselenol generated with seleno-L-methionine as a substrate for L-methionine-alpha-deamino-gamma-mercaptomethane lyase (EC4.4.1.11, also known as methioninase). Exposure of DU145 cells to methylselenol so generated in the sub-micromolar range led to caspase-mediated cleavage of poly(ADP-ribose) polymerase, nucleosomal DNA fragmentation, and morphologic apoptosis and resulted in a profile of biochemical effects similar to that of methylseleninic acid (MSeA) exposure as exemplified by the inhibition of phosphorylation of protein kinase AKT and extracellularly regulated kinases 1/2. In HUVEC, methylselenol exposure recapitulated the G1 arrest action of MSeA in mitogen-stimulated G1 progression during mid-G1 to late G1. This stage specificity was mimicked by inhibitors of phosphatidylinositol 3-kinase. The results support methylselenol as an active selenium metabolite for inducing caspase-mediated apoptosis and cell-cycle G1 arrest. This cell-free methylselenol-generation system is expected to have significant usefulness for studying the biochemical and molecular targeting mechanisms of this critical metabolite and may constitute the basis of a novel therapeutic approach for cancer, using seleno-L-methionine as a prodrug.

• Authors: Zaisen Wang, Cheng Jiang, Junxuan Lü
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 34 Issue 3 Pg. 113-20 (Jul 2002) ISSN: 0899-1987 [Print] United States
• PMID: 12112305 (Publication Type: Journal Article)
• Copyright: Copyright 2002 Wiley-Liss, Inc.

Chemical References

• Organoselenium Compounds
• Proto-Oncogene Proteins
• methylserine phosphate
• Phosphoserine
• methaneselenol
• Selenomethionine
• methylselenic acid
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• Caspases
• Carbon-Sulfur Lyases
• L-methionine gamma-lyase
• Selenium
• Methanol

Topics

• Apoptosis (drug effects, physiology)
• Carbon-Sulfur Lyases (metabolism)
• Caspases (metabolism)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Endothelium, Vascular (cytology, drug effects)
• G1 Phase (drug effects, physiology)
• Humans
• Methanol (analogs & derivatives, metabolism, pharmacology)
• Mitogen-Activated Protein Kinase 1 (drug effects, metabolism)
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases (drug effects, metabolism)
• Organoselenium Compounds (metabolism, pharmacology)
• Phosphorylation
• Phosphoserine
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins (drug effects, metabolism)
• Proto-Oncogene Proteins c-akt
• S Phase (drug effects)
• Selenium (metabolism)
• Selenomethionine (metabolism)