Sodium arsenite alters cell cycle and MTHFR, MT1/2, and c-Myc protein levels in MCF-7 cells.
There is limited available information on the effects of arsenic on enzymes participating in the folate cycle. Therefore, our aim was to evaluate the effects of sodium arsenite on the protein levels of methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR) and its further relationship with the expression MT1/2 and c-myc in MCF-7 cells. Arsenite treatment (0-10 microM) for 4 h decreased MTHFR levels in a concentration-dependent fashion without significant effects on DHFR. The effects on MTHFR were observed at arsenite concentrations not significantly affecting cell viability. We also observed an increase in S-phase recruitment at all concentrations probed. Lower concentrations (<5 microM) induced cell proliferation, showing a high proportion of BrdU-stained cells, indicating a higher DNA synthesis rate. However, higher concentrations (> or =5 microM) or longer treatment periods induced apoptosis. Arsenite also induced dose-dependent increases in MT1/2 and c-Myc protein levels. The levels of MTHFR were inversely correlated to MT1/2 and c-Myc overexpression and increased S-phase recruitment. Our findings indicate that breast epithelial cells are responsive to arsenite and suggest that exposure may pose a risk for breast cancer. The reductions in MTHFR protein levels contribute to understand the mechanisms underlying the induction of genes influencing growth regulation, such as c-myc and MT1/2. However, further research is needed to ascertain if the effects here reported following short-time and high-dose exposure are relevant for human populations chronically exposed to low arsenic concentrations.
Ruiz-Ramos
Ruben
R
Centro de Investigación en Salud Poblacional, INSP, Cuernavaca, Morelos, México.
López-Carrillo
Lizbeth
L
Albores
Arnulfo
A
Hernández-Ramírez
Raúl U
RU
Cebrian
Mariano E
ME
D000963:Antimetabolites; D018053:Arsenites / Q000633:toxicity*; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008668:Metallothionein / Q000096:biosynthesis*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000096:biosynthesis*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D016196:S Phase / Q000187:drug effects; D017670:Sodium Compounds / Q000633:toxicity*
D000963:Antimetabolites; D018053:Arsenites; D016271:Proto-Oncogene Proteins c-myc; D017670:Sodium Compounds; C017947:sodium arsenite; D008668:Metallothionein; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D001973:Bromodeoxyuridine