Department of Pharmacology, College of Medicine and Intractable Disease Research Center, Dongguk University, Gyeongju, 780-714, Korea.
Mol Biol Rep. 2013 Oct;40(10):5959-66. doi: 10.1007/s11033-013-2705-1. Epub 2013 Sep 25.
We investigated the effects of starfish (Asterina pectinifera) polysaccharides on metastatic activity in MCF-7 estrogen receptor (ER)-positive human breast cancer cells. In wound healing assay, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell migration was dose-dependently decreased by the starfish polysaccharides (PS). Transcription of aromatase, which catalyzes estrogen synthesis from androgen, was reduced by PS. Also, transcription of TPA-induced cyclooxygenase-2 (COX-2), which enhances breast cancer progression and metastasis via the increase of prostaglandin E2 biosynthesis, was downregulated by the PS in a dose-dependent manner. PS decreased the expression and activity of matrix metalloproteinase (MMP)-9, an important factor in the degradation of basement membrane and extracellular matrix in the metastasis process. In contrast, mRNA expression of tissue inhibitor of matrix metalloproteinase (TIMP)-1, a MMP inhibitor, was increased by 10-120 μg/ml of PS but not that of TIMP-2. We also found that PS reversed the phosphorylations of p38, ERK and JNK but not IκBα and NF-κB. These results demonstrate that PS successfully inhibits PKC-mediated cell migration and metastatic activities in MCF-7 ER-positive human breast cancer cells via downregulation of MMP-9 activity mediated by TIMP-1 upregulation and inhibition of aromatase and COX-2 expression. Also, COX-2 and MMP-9 expressions are attenuated through the inhibition of AP-1 transcription activity via the downregulation of c-Jun expression regulated by p38, ERK and JNK signaling. In conclusion, the present investigation shows that PS may prevent COX-2- and MMP-9-mediated metastatic activities in MCF-7 ER-positive breast cancer cells through the downregulation of MAPK signaling pathways.
我们研究了海星（Asterina pectinifera）多糖对 MCF-7 雌激素受体（ER）阳性人乳腺癌细胞转移活性的影响。在划痕愈合试验中，海星多糖（PS）剂量依赖性地降低了 12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的细胞迁移。芳香酶的转录，该酶将雄激素合成为雌激素，被 PS 降低。此外，PS 还以剂量依赖性方式下调了 TPA 诱导的环氧化酶-2（COX-2）的转录，COX-2 通过增加前列腺素 E2 的生物合成来增强乳腺癌的进展和转移。PS 降低了基质金属蛋白酶（MMP）-9 的表达和活性，MMP-9 是转移过程中基底膜和细胞外基质降解的重要因素。相比之下，PS 增加了组织抑制剂基质金属蛋白酶（TIMP）-1 的 mRNA 表达，而不是 TIMP-2 的表达，10-120μg/ml 的 PS 即可增加 TIMP-1 的表达。我们还发现 PS 逆转了 p38、ERK 和 JNK 的磷酸化，但没有 IκBα 和 NF-κB 的磷酸化。这些结果表明，PS 通过上调 TIMP-1 抑制 MMP-9 活性，抑制芳香酶和 COX-2 的表达，成功抑制了 PKC 介导的 MCF-7 ER 阳性人乳腺癌细胞的迁移和转移活性。此外，通过下调 c-Jun 表达，抑制 AP-1 转录活性，从而抑制 COX-2 和 MMP-9 的表达。总之，本研究表明 PS 可能通过下调 MAPK 信号通路来预防 COX-2 和 MMP-9 介导的 MCF-7 ER 阳性乳腺癌细胞的转移活性。
