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Induction of caspase‐mediated apoptosis and cell‐cycle G 1 arrest by selenium metabolite methylselenol
Author(s) -
Wang Zaisen,
Jiang Cheng,
Lü Junxuan
Publication year - 2002
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.10056
Subject(s) - du145 , biology , apoptosis , poly adp ribose polymerase , dna fragmentation , cell cycle checkpoint , cell cycle , cancer cell , kinase , microbiology and biotechnology , biochemistry , programmed cell death , cancer research , enzyme , cancer , polymerase , lncap , genetics
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 G 1 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 G 1 arrest effect on the human umbilical vein endothelial cells (HUVECs) of methylselenol generated with seleno‐ L ‐methionine as a substrate for L ‐methionine‐α‐deamino‐γ‐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 G 1 arrest action of MSeA in mitogen‐stimulated G 1 progression during mid‐G 1 to late G 1 . 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 G 1 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. © 2002 Wiley‐Liss, Inc.