15-Deoxi-Delta(12,14)-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.
Cocca
Claudia
C
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid and Centro de Investigación Biomédica en Red sobre Enfermedades neurodegenerativas (CIBERNED), Arturo Duperier, 4, 28029 Madrid, Spain.
Dorado
Jorge
J
Calvo
Enrique
E
López
Juan Antonio
JA
Santos
Angel
A
Perez-Castillo
Ana
A
D001665:Binding Sites; D019921:Biotinylation; D015153:Blotting, Western; D016923:Cell Death; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D008958:Models, Molecular; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D047495:PPAR gamma; D014404:Tubulin; D050257:Tubulin Modulators; D015230:Prostaglandin D2