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Arsenic targets tubulins to induce apoptosis in myeloid leukemia cells
1Department of Laboratories, North Shore University Hospital, Manhasset, New York 11030, USA. YMLI@AOL.COM
Abstract:
Arsenic exhibits a differential toxicity to cancer cells. At a high concentration (>5 microM), As2O3 causes acute necrosis in various cell lines. At a lower concentration (0.5-5 microm), it induces myeloid cell maturation and an arrest in metaphase, leading to apoptosis. As2O3-treated cells have features found with both tubulin-assembling enhancers (Taxol) and inhibitors (colchicine). Prior treatment of monomeric tubulin with As2O3 markedly inhibits GTP-induced polymerization and microtubule formation in vitro but does not destabilize GTP-induced tubulin polymers. Cross-inhibition experiments indicate that As2O3 is a noncompetitive inhibitor of GTP binding to tubulin. These observations correlate with the three-dimensional structure of beta-tubulin and suggest that the cross-linking of two vicinal cysteine residues (Cys-12 and Cys-213) by trivalent arsenic inactivates the GTP binding site. Furthermore, exogenous GTP can prevent As2O3-induced mitotic arrest.
Insights
Arsenic trioxide (As2O3) affects cancer cells differently based on concentration. Lower doses induce cell maturation and apoptosis by inhibiting GTP binding to tubulin, crucial for cell division.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Arsenic trioxide (As2O3) displays differential toxicity towards cancer cells.
- Observed effects include necrosis at high concentrations and myeloid cell maturation/apoptosis at lower concentrations.
Purpose of the Study:
- To elucidate the molecular mechanism of As2O3-induced effects on cancer cells, specifically its interaction with tubulin.
- To investigate As2O3's role in microtubule dynamics and cell cycle arrest.
Main Methods:
- In vitro polymerization assays of purified tubulin.
- GTP binding inhibition experiments.
- Analysis of As2O3 effects on cell cycle progression and microtubule structure.
Main Results:
- As2O3 inhibits GTP-induced tubulin polymerization and microtubule formation without destabilizing existing polymers.
- As2O3 acts as a noncompetitive inhibitor of GTP binding to tubulin.
- Structural analysis suggests As2O3 cross-links cysteine residues (Cys-12 and Cys-213) in beta-tubulin, inactivating the GTP binding site.
Conclusions:
- As2O3 disrupts microtubule dynamics by interfering with GTP binding to tubulin.
- This mechanism underlies the observed As2O3-induced mitotic arrest and apoptosis in cancer cells.
- Exogenous GTP can rescue cells from As2O3-induced mitotic arrest, confirming the target interaction.