Azuma Yasutaka, Watanabe Kyoko, Date Masataka, Daito Michiharu, Ohura Kiyoshi
Department of Pharmacology, Osaka Dental University, Japan.
J Pharmacol Sci. 2004 Mar;94(3):261-70. doi: 10.1254/jphs.94.261.
15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ2), which is a ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), induced apoptosis of several human tumors including gastric, lung, colon, prostate, and breast. However, the role of PPARgamma signals in other types of cancer cells (e.g., leukemia) except solid cancer cells is still unclear. The aim of this study is to evaluate the ability of 15dPGJ2 to modify the proliferation of the human leukemia cell line THP-1. 15dPGJ2 at 5 microM stimulated the proliferation in THP-1 at 24 to 72 h after incubation. In contrast, 15dPGJ2 at concentrations above 10 microM inhibited the proliferation through the induction of apoptosis. PGD2, PGJ2, and Delta12-PGJ2 (DeltaPGJ2), precursors of 15dPGJ2, had similar proliferative effects at lower concentrations, whereas they induced apoptosis at high concentrations. 15dPGJ2 and three precursors failed to induce the differentiation in THP-1 as assessed by using the differentiation marker CD11b. FACScan analysis revealed that PGD2 at 5 microM, PGJ2 at 1 microM, DeltaPGJ2 at 1 microM and 15dPGJ2 at 5 microM all accelerated cell cycle progression in THP-1. Immunoblotting analysis revealed that PGD2 at 5 microM and 15dPGJ2 at 5 microM inhibited the expression of phospho-p38, phospho-MKK3/MKK6, and phospho-ATF-2, and the expression of Cdk inhibitors including p18, p21, and p27 in THP-1. In contrast, PGJ2 at 1 microM and DeltaPGJ2 at 1 microM did not affect their expressions. These results suggest that 15dPGJ2 and PGD2 may, through inactivation of the p38 mitogen-activated protein kinase pathway, inhibit the expression of Cdk inhibitors, leading to acceleration of the THP-1 proliferation.
15-脱氧-Δ(12,14)-前列腺素J2（15dPGJ2）是过氧化物酶体增殖物激活受体γ（PPARγ）的配体，可诱导包括胃癌、肺癌、结肠癌、前列腺癌和乳腺癌在内的多种人类肿瘤细胞凋亡。然而，除实体癌细胞外，PPARγ信号在其他类型癌细胞（如白血病细胞）中的作用仍不清楚。本研究的目的是评估15dPGJ2对人白血病细胞系THP-1增殖的影响。5微摩尔的15dPGJ2在孵育后24至72小时刺激THP-1细胞增殖。相反，浓度高于10微摩尔的15dPGJ2通过诱导凋亡抑制细胞增殖。15dPGJ2的前体PGD2、PGJ2和Δ12-PGJ2（ΔPGJ2）在较低浓度时具有相似的增殖作用，而在高浓度时则诱导凋亡。通过使用分化标志物CD11b评估，15dPGJ2及其三种前体均未诱导THP-1细胞分化。流式细胞仪分析显示，5微摩尔的PGD2、1微摩尔的PGJ2、1微摩尔的ΔPGJ2和5微摩尔的15dPGJ2均加速了THP-1细胞的细胞周期进程。免疫印迹分析显示，5微摩尔的PGD2和5微摩尔的15dPGJ2抑制了THP-1细胞中磷酸化p38、磷酸化MKK3/MKK6和磷酸化ATF-2的表达，以及包括p18、p21和p27在内的细胞周期蛋白依赖性激酶抑制剂的表达。相反，1微摩尔的PGJ2和1微摩尔的ΔPGJ2对它们的表达没有影响。这些结果表明，15dPGJ2和PGD2可能通过使p38丝裂原活化蛋白激酶途径失活，抑制细胞周期蛋白依赖性激酶抑制剂的表达，从而导致THP-1细胞增殖加速。
