Mechanism of Antineoplastic Action of Bisperoxovanadium Compound

摘要

This work describes studies into the mechanism of action of bisperoxovanadium (bpVs) compounds and into the basic biology and regulation of Cdc25A phosphatase. The bpVs cause phase-specific cell cycle arrest (G1/S), dose-dependent inhibition of Cdk activity, and persistent Rb hypophosphorylation upon release from serum starvation, consistent with Cdc25A inhibition. Further, they cause p53-independent apoptosis. Oxidative stress and DNA damage do not appear to be involved in their mechanism of action, given that: p53 is not induced by bpV(Me2Phen); p53 and p21 status do not affect IC50; depletion of glutathione or supplementation with antioxidants does not affect IC50, in contrast to other heavy metal-based agents. With respect to regulation, the Cdc25A nuclear localization signal (NLS) was identified and characterized. Data suggest that phosphorylation of S292, adjacent to the NLS, may promote nuclear localization. In the unperturbed cell cycle, S292 phosphorylation, a Chk1/2 target, appears to label sites of local inhibition of Cdc25A, suggesting fine tuning of the Cdc25-Cdk axis at the scale of specific subnuclear and mitotic structures.