Biotinylation enhances the anticancer effects of 15d-PGJ2 against breast cancer cells

15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a natural agonist of peroxisome proliferator-Activated receptor γ (PPARγ) that displays anticancer activity. Various studies have indicated that the effects of 15d-PGJ2 are due to both PPARγ- dependent and -independent mechanisms. In the present study, we examined the effects of a biotinylated form of 15d-PGJ2 (b-15d-PGJ2) on hormone-dependent MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines. b-15d-PGJ2 inhibited cell proliferation more efficiently than 15d-PGJ2 or the synthetic PPARγ agonist, efatutazone. b-15d-PGJ2 was also more potent than its non-biotinylated counterpart in inducing apoptosis. We then analyzed the mechanisms underlying this improved efficiency. It was found not to be the result of biotin receptor-mediated increased incorporation, since free biotin in the culture medium did not decrease the anti-proliferative activity of b-15d-PGJ2 in competition assays. Of note, b-15d-PGJ2 displayed an improved PPARγ agonist activity, as measured by transactivation experiments. Molecular docking analyses revealed a similar insertion of b-15d-PGJ2 and 15d-PGJ2 into the ligand binding domain of PPARγ via a covalent bond with Cys285. Finally, PPARγ silencing markedly decreased the cleavage of the apoptotic markers, poly(ADP-ribose) polymerase 1 (PARP-1) and caspase-7, that usually occurs following b-15d-PGJ2 treatment. Taken together, our data indicate that biotinylation enhances the anti-proliferative and pro-Apoptotic activity of 15d-PGJ2, and that this effect is partly mediated via a PPARγ-dependent pathway. These results may aid in the development of novel therapeutic strategies for breast cancer treatment.