Inhibition of activator protein 1 activation, vascular endothelial growth factor, and cyclooxygenase-2 expression by 15-deoxy-Δ12,14-prostaglandin J2 in colon carcinoma cells:: Evidence for a redox-sensitive peroxisome proliferator-activated receptor-γ-independent mechanism
Inhibition of activator protein 1 activation, vascular endothelial growth factor, and cyclooxygenase-2 expression by 15-deoxy-Δ12,14-prostaglandin J2 in colon carcinoma cells:: Evidence for a redox-sensitive peroxisome proliferator-activated receptor-γ-independent mechanism
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DOI：
10.1158/0008-5472.can-04-0849
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发表时间：
2004-08-01
期刊：
影响因子：
11.2
通讯作者：
Fresno, M
中科院分区：
文献类型：
--
作者：
Grau, R;Iñiguez, MA;Fresno, M
环氧合酶（考克斯）-2和血管内皮生长因子（VEGF）与肿瘤的生长和转移密切相关。在这里，我们发现佛波酯介导的结肠癌细胞中VEGF和考克斯-2表达的诱导被15-脱氧-Delta（12），（14）-前列腺素J（2）（15 d-PGJ（2））抑制。这种环戊烯酮能够抑制由佛波醇12-肉豆蔻酸13-乙酸酯（PMA）或c-Jun过表达诱导的考克斯-2和VEGF启动子的激活蛋白1（AP-1）依赖性转录诱导。15 d-PGJ（2）干扰了导致AP-1活化的信号通路中的至少两个步骤。首先，15 d-PGJ（2）损害AP-1与共有DNA序列的结合。第二，15 d-PGJ（2）选择性抑制c-Jun氨基末端激酶（JNK），但不抑制PMA诱导的细胞外信号调节激酶或p38丝裂原活化蛋白激酶活化。这导致JNK磷酸化c-Jun并激活其反式激活活性的能力降低。发现该环戊烯酮对AP-1活化和考克斯-2或VEGF转录诱导的抑制不依赖于过氧化物酶体增殖物激活受体-γ（PPARgamma），因为它不受PPARgamma的显性负性形式的表达或PPARgamma拮抗剂的使用的影响。相反，我们发现15 d-PGJ（2）对AP-1激活的影响可能是通过其诱导细胞内氧化应激的能力发生的。抗氧化剂N-乙酰半胱氨酸显著逆转了15 d-PGJ（2）对AP-1活性和考克斯-2或VEGF转录诱导的抑制。总之，这些发现通过抑制参与肿瘤进展的AP-1依赖性基因（如考克斯-2和VEGF）的诱导，为15 d-PGJ（2）的抗肿瘤特性提供了新的见解。
Cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF) are significantly associated with tumor growth and metastasis. Here we show that phorbol ester-mediated induction of VEGF and COX-2 expression in colon carcinoma cells is inhibited by 15-deoxy-Delta(12),(14)-prostaglandin J(2) (15d-PGJ(2)). This cyclopentenone was able to inhibit activator protein1 (AP-1)-dependent transcriptional induction of COX-2 and VEGF promoters induced by phorbol 12-myristate 13-acetate (PMA) or c-Jun overexpression. 15d-PGJ(2) interfered with at least two steps within the signaling pathway leading to AP-1 activation. First, 15d-PGJ(2) impaired AP-1 binding to a consensus DNA sequence. Second, 15d-PGJ(2) selectively inhibited c-Jun NH2 terminal kinase (JNK) but not extracellular signal-regulated kinase or p38 mitogen-activated protein kinase activation induced by PMA. This led to a decreased ability of JNK to phosphorylate c-Jun and to activate its transactivating activity. Inhibition of AP-1 activation and COX-2 or VEGF transcriptional induction by this cyclopentenone was found to be independent of peroxisome proliferator-activated receptor-gamma (PPARgamma) because it was not affected by either expression of a dominant negative form of PPARgamma or the use of a PPARgamma antagonist. In contrast, we have found that the effects of 15d-PGJ(2) on AP-1 activation may occur through its ability to induce intracellular oxidative stress. The antioxidant N-acetylcysteine significantly reversed the inhibition by 15d-PGJ(2) of AP-1 activity and COX-2 or VEGF transcriptional induction. Together, these findings provide new insight into the antitumoral properties of 15d-PGJ(2) through the inhibition of the induction of AP-1-dependent genes involved in tumor progression, such as COX-2 and VEGF.