Li Xiuling, Wei Jingyan, Tai Hsin-Hsiung
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
Arch Biochem Biophys. 2007 Nov 1;467(1):20-30. doi: 10.1016/j.abb.2007.08.005. Epub 2007 Aug 22.
Both 12-hydroxyheptadecatrienoic acid (12-HHT) and thromboxane A2 (TXA2) are products derived from prostaglandin H2 (PGH2) catalyzed by thromboxane synthase. Whether or not they exhibit similar actions remains to be determined. While TXA2-induced activation of extracellular signal-regulated kinases (ERKs) has been extensively studied, 12-HHT-induced activation of ERKs has not been explored. We reported for the first time that 12-HHT induced activation of ERKs in human prostate cancer cell line, PC3. We also compared the mechanisms of 12-HHT- and I-BOP-, a TXA2 mimetic, mediated ERK activation in PC3 cells. The activation of ERKs induced by either agent was shown to involve protein kinase C (PKC)-, protein kinase A (PKA)-, Src kinase and phosphoinositide-3 kinase (PI-3K)-dependent mechanisms in addition to the transactivation of the EGF receptor (EGFR) and the involvement of matrix metalloproteinases (MMPs) based on the sensitivity of the activation to their respective inhibitors. JNK/SAPK and p38 MAPK pathways were responsive to I-BOP but not to 12-HHT stimulation. Both 12-HHT- and I-BOP-induced activations of ERKs were also examined in other human prostate cancer cells, human lung cancer cells, and human lung fibroblast. I-BOP appeared to induce activation of ERKs in most cell lines, whereas 12-HHT induced activation of ERKs only in lung fibroblast in addition to PC3 cells. It appears that TPs are more generally expressed and the potential 12-HHT receptor (s) is expressed in limited specific cell types. Our results suggest that increased expression of thromboxane synthase as seen in prostate tumor may stimulate tumorigenesis as a consequence of concurrent increased synthesis of two fatty acids capable of activating ERKs.
12-羟基十七碳三烯酸（12-HHT）和血栓素A2（TXA2）均为由血栓素合酶催化前列腺素H2（PGH2）生成的产物。它们是否具有相似作用仍有待确定。虽然TXA2诱导的细胞外信号调节激酶（ERK）激活已得到广泛研究，但12-HHT诱导的ERK激活尚未被探索。我们首次报道12-HHT可诱导人前列腺癌细胞系PC3中ERK的激活。我们还比较了12-HHT和TXA2模拟物I-BOP在PC3细胞中介导ERK激活的机制。结果显示，两种试剂诱导的ERK激活均涉及蛋白激酶C（PKC）、蛋白激酶A（PKA）、Src激酶和磷酸肌醇-3激酶（PI-3K）依赖性机制，此外还涉及表皮生长因子受体（EGFR）的反式激活以及基质金属蛋白酶（MMP）的参与，这基于激活对各自抑制剂的敏感性。JNK/SAPK和p38 MAPK通路对I-BOP有反应，但对12-HHT刺激无反应。我们还在其他人类前列腺癌细胞、人类肺癌细胞和人肺成纤维细胞中检测了12-HHT和I-BOP诱导的ERK激活。I-BOP似乎可在大多数细胞系中诱导ERK激活，而12-HHT仅在PC3细胞及肺成纤维细胞中诱导ERK激活。看来TPs更普遍表达，而潜在的12-HHT受体仅在有限的特定细胞类型中表达。我们的结果表明，如在前列腺肿瘤中所见的血栓素合酶表达增加，可能由于同时增加合成两种能够激活ERK的脂肪酸而刺激肿瘤发生。
