15-Deoxi-Δ12,14-prostaglandin J2 is a tubulin-binding agent that destabilizes microtubules and induces mitotic arrest

El pdf del artículo es el manuscrito final de autor.15-Deoxi-Δ12,14-prostaglandin J2 (15d-PGJ2) is known to play an important role in the pathophysiology of carcinogenesis, however, the molecular mechanisms underlying these effects are not yet fully understood. Recently, we have shown that 15d-PGJ2 is a potent inducer of breast cancer cell death and that this effect is associated with a disruption of the microtubule cytoskeletal network. Here, we show that treatment of the MCF-7 breast cancer cell line with 15d-PGJ2 induces an accumulation of cells in the G2/M compartment of the cell cycle and a marked disruption of the microtubule network. 15d-PGJ2 treatment causes mitotic abnormalities that consist of failure to form a stable metaphase plate, incapacity to progress through anaphase, and failure to complete cytokinesis. 15d-PGJ2 binds to tubulin through the formation of a covalent adduct with at least four cysteine residues in α- and β-tubulin, as detected by hybrid triple-quadrupole mass spectrometry analysis. Overall, these results support the hypothesis that microtubule disruption and mitotic arrest, as a consequence of the binding of 15d-PGJ2 to tubulin, can represent one important pathway leading to breast cancer cell death.This work was supported by the Ministerio de Educacion y Ciencia grants SAF2004-06263-CO2-01 and SAF2007-62811 (to A.P.-C) and SAF2004-06263-CO2-02 (to A.S.), and the Fondo de Investigaciones Sanitarias grant PIO40682 (to A.P.-C).Peer Reviewe

15-Deoxi-Δ12,14-prostaglandin J2 is a tubulin-binding agent that destabilizes microtubules and induces mitotic arrest

15-Deoxi-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is known to play an important role in the pathophysiology of carcinogenesis, however, the molecular mechanisms underlying these effects are not yet fully understood. Recently, we have shown that 15d-PGJ(2) is a potent inducer of breast cancer cell death and that this effect is associated with a disruption of the microtubule cytoskeletal network. Here, we show that treatment of the MCF-7 breast cancer cell line with 15d-PGJ(2) induces an accumulation of cells in the G(2)/M compartment of the cell cycle and a marked disruption of the microtubule network. 15d-PGJ(2) treatment causes mitotic abnormalities that consist of failure to form a stable metaphase plate, incapacity to progress through anaphase, and failure to complete cytokinesis. 15d-PGJ(2) binds to tubulin through the formation of a covalent adduct with at least four cysteine residues in alpha- and beta-tubulin, as detected by hybrid triple-quadrupole mass spectrometry analysis. Overall, these results support the hypothesis that microtubule disruption and mitotic arrest, as a consequence of the binding of 15d-PGJ(2) to tubulin, can represent one important pathway leading to breast cancer cell death.Fil: Cocca, Claudia Marcela. Universidad Autónoma de Madrid; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Dorado, Jorge. Universidad Autónoma de Madrid; EspañaFil: Calvo, Enrique. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: López, Juan Antonio. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Santos, Angel. Universidad Complutense de Madrid; EspañaFil: Perez Castillo, Ana. Universidad Autónoma de Madrid; Españ