title: 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.
abstract: 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.
authors.affiliation: Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan.
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Kamagata
authors.forename: Naoki
authors.initials: N
authors.lastname: Tsuji
authors.forename: Mikako
authors.initials: M
authors.lastname: Moriai
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kobayashi
authors.forename: Naoki
authors.initials: N
authors.lastname: Watanabe
mesh_terms: D017209:Apoptosis / Q000502:physiology; D064107:Aurora Kinase B; D064127:Aurora Kinases; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019926:Cyclin B / Q000096:biosynthesis*; D056744:Cyclin B1; D015536:Down-Regulation; D005260:Female; D016195:G2 Phase / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077022:Survivin
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; C107489:BIRC5 protein, human; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D015230:Prostaglandin D2