15-deoxy-Delta(12,14)-prostaglandin J2 inhibits G2-M phase progression in human breast cancer cells via the down-regulation of cyclin B1 and survivin expression.

The cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) exerts a growth inhibitory effect on cancer cells, and this effect is linked to the induction of apoptosis or cell cycle arrest. Induction of apoptosis by 15d-PGJ(2) is associated with the down-regulation of anti-apoptotic proteins. G(0)-G(1)-->S phase progression is inhibited by 15d-PGJ(2) via the degradation of cyclin D1. In this study, we further investigated the mechanism by which 15d-PGJ(2) inhibits cancer cell growth by using the breast cancer cell lines MCF-7 and T-47D. Treatment with 20 microM 15d-PGJ(2) for 72 h completely blocked the growth in both cell lines. However, the proportions of apoptotic MCF-7 and T-47D cells were 21.1% and 40.9%, respectively, indicating that the induction of apoptosis did not appear to fully account for growth inhibition by 15d-PGJ(2). Cell cycle analysis using cells synchronized at the G(0)-G(1) or S phase revealed that 15d-PGJ(2) blocked not only G(0)-G(1)-->S phase progression but also G(2)-M phase progression. The expression of both cyclins D1 and B1 was decreased by 15d-PGJ(2). Furthermore, 15d-PGJ(2) inhibited aurora-B kinase activity, which coincided with the down-regulation of survivin. Thus, 15d-PGJ(2) induced cell cycle arrest at the G(2)-M phase via inhibition of cyclin B1 expression and aurora-B kinase activity. We conclude that survivin may be an important target for 15d-PGJ(2), and its down-regulation may lead to a decrease in aurora-B kinase activity.