Kamagata Chinatsu, Tsuji Naoki, Moriai Mikako, Kobayashi Daisuke, Watanabe Naoki
Department of Clinical Laboratory Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan.
Breast Cancer Res Treat. 2007 May;102(3):263-73. doi: 10.1007/s10549-006-9336-3. Epub 2006 Sep 21.
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.
环戊烯酮前列腺素15-脱氧-Δ（12,14）-前列腺素J2（15d-PGJ2）对癌细胞具有生长抑制作用，且这种作用与诱导细胞凋亡或细胞周期停滞有关。15d-PGJ2诱导的细胞凋亡与抗凋亡蛋白的下调有关。15d-PGJ2通过降解细胞周期蛋白D1抑制G（0）-G（1）期向S期的进展。在本研究中，我们使用乳腺癌细胞系MCF-7和T-47D进一步研究了15d-PGJ2抑制癌细胞生长的机制。用20μM 15d-PGJ2处理72小时完全阻断了两种细胞系的生长。然而，凋亡的MCF-7和T-47D细胞比例分别为21.1%和40.9%，这表明细胞凋亡的诱导似乎不能完全解释15d-PGJ2对生长的抑制作用。对在G（0）-G（1）期或S期同步化的细胞进行细胞周期分析发现，15d-PGJ2不仅阻断了G（0）-G（1）期向S期的进展，还阻断了G（2）-M期的进展。细胞周期蛋白D1和B1的表达均被15d-PGJ2下调。此外，15d-PGJ2抑制极光激酶B的活性，这与生存素的下调相一致。因此，15d-PGJ2通过抑制细胞周期蛋白B1的表达和极光激酶B的活性诱导细胞周期停滞在G（2）-M期。我们得出结论，生存素可能是15d-PGJ2的一个重要靶点，其下调可能导致极光激酶B活性降低。
