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Down-regulation of wt1 expression in leukemia cell lines as part of apoptotic effect in arsenic treatment using two
Wolfgang Glienke1, Kai U Chow, Nina Bauer
1Department of Internal Medicine II, Hematology and Oncology, University Hospital, Johann Wolfgang Goethe University, Frankfurt, Germany.
Abstract:
Arsenic trioxide (As2O3) induces remission in patients with acute promyelocytic leukemia (APL). To better understand molecular mechanisms of arsenic actions, this study investigated the effect of two different arsenic compounds on gene expression of apoptosis and cellular proliferation related genes. The Wilms' tumor gene (wt1) is up-regulated in acute myeloid leukemia (AML) and a variety of leukemia cell lines. The expression of wt1 in these cells is proposed to have an anti-apoptotic effect. HL-60 and K562 were treated with arsenic trioxide (As2O3) and sodium arsenite (NaAsO2) at concentrations between 0 - 10 microM for up to 48 h. The induction of apoptosis was accompanied by down-regulation of hTERT and wt1 mRNA and protein expression but up-regulation of par-4. Low concentrations of 0.1 microM arsenic induced expression of the anti-apoptotic bcl-2 gene in both cell lines HL-60 and K562. There were no major differences encountered between compounds. After arsenic treatment of the leukemia cell lines HL-60 and K562 the up-regulation of par-4 may contribute to the induction of apoptosis rather than down-regulation of bcl-2. The therapeutic effect of arsenic is the induction of apoptosis by modulating the gene expression profile of pro- and anti-apoptotic genes including the wt1 gene.
Insights
Arsenic compounds induce apoptosis in leukemia cells by altering gene expression. This study shows arsenic trioxide and sodium arsenite down-regulate Wilms
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Arsenic trioxide (As2O3) is effective in treating acute promyelocytic leukemia (APL).
- The Wilms' tumor gene (wt1) is implicated in acute myeloid leukemia (AML) and may promote cell survival.
- Understanding arsenic's molecular mechanisms requires investigating its effects on apoptosis and proliferation genes.
Purpose of the Study:
- To investigate the effects of arsenic trioxide (As2O3) and sodium arsenite (NaAsO2) on gene expression related to apoptosis and cellular proliferation.
- To elucidate the role of Wilms' tumor gene (wt1) expression in arsenic-induced apoptosis in leukemia cell lines.
Main Methods:
- Treatment of HL-60 and K562 leukemia cell lines with As2O3 and NaAsO2 at concentrations ranging from 0 to 10 microM for up to 48 hours.
- Analysis of mRNA and protein expression levels of key apoptosis-related genes, including wt1, hTERT, par-4, and bcl-2.
Main Results:
- Arsenic treatment led to apoptosis induction, accompanied by down-regulation of hTERT and wt1 mRNA and protein.
- Up-regulation of the pro-apoptotic gene par-4 was observed following arsenic treatment.
- Low arsenic concentrations (0.1 microM) induced the anti-apoptotic bcl-2 gene; no significant differences were noted between the two arsenic compounds.
Conclusions:
- Arsenic compounds modulate the gene expression profile of pro- and anti-apoptotic genes, including wt1, contributing to therapeutic effects in leukemia.
- The up-regulation of par-4 appears to be a significant factor in arsenic-induced apoptosis, potentially more so than the down-regulation of bcl-2.
- Arsenic's therapeutic action in leukemia involves inducing apoptosis through the modulation of critical gene expression pathways.
