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| 題名: | Magnolol down-regulates HER2 gene expression, leading to inhibition of HER2-mediated metastatic potential in ovarian cancer cells |
| 作者: | Chuang, Tzu-Chao;Hsu, Shih-Chung;Cheng, Yi-Ting;Shao, Wei-Syun;Wu, Kuohui;Fang, Guan-Shiun;Ou, Chien-Chih;Wang, Vinchi |
| 貢獻者: | 淡江大學化學學系 |
| 關鍵詞: | Magnolol;HER2;Metastatic potential;Ovarian cancer |
| 日期: | 2011-12-01 |
| 上傳時間: | 2012-04-12 11:51:43 (UTC+8) |
| 出版者: | Shannon: Elsevier Ireland Ltd |
| 摘要: | Overexpression of the HER2 oncogene contributes to tumor cell invasion, metastasis and angiogenesis and correlates with poor prognosis. Magnolol has been reported to exhibit anti-tumor activities. However, the molecular mechanism of action of magnolol has not been investigated in HER2-positive cancer cells. Therefore, we examined the anti-cancer effects of magnolol on HER2-overexpressing ovarian cancer cells. Magnolol treatment caused a dose-dependent inhibition of HER2 gene expression at the transcriptional level, potentially in part through suppression of NF-κB activation. Treatment of HER2-overexpressing ovarian cancer cells with magnolol down-regulated the HER2 downstream PI3K/Akt signaling pathway, and suppressed the expression of downstream target genes, vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2) and cyclin D1. Consistently, magnolol-mediated inhibition of MMP2 activity could be prevented by co-treatment with epidermal growth factor. Migration assays revealed that magnolol treatment markedly reduced the motility of HER2-overexpressing ovarian cancer cells. Furthermore, magnolol-induced apoptosis in HER2-overexpressing ovarian cancer cells was characterized by the up-regulation of cleaved poly(ADP-ribose) polymerase (PARP) and activated caspase 3. These findings suggest that magnolol may act against HER2 and its downstream PI3K/Akt/mTOR-signaling network, thus resulting in suppression of HER2-mediated transformation and metastatic potential in HER2-overexpressing ovarian cancers. These results provide a novel mechanism to explain the anti-cancer effect of magnolol.
神經膠原致癌基因(HER2)過表現會導致癌細胞的侵入、轉移和血管新生，因而病患的預後較差。厚朴酚(Magnolol)雖已被證實有抗癌的活性；然而，厚朴酚在神經膠原致癌基因過表現癌細胞的作用分子機制未知。我們利用神經膠原致癌基因過表現卵巢細胞株來研究厚朴酚在神經膠原致癌基因過表現癌細胞抗癌作用的分子機轉。本研究證明厚朴酚可藉由抑制NF-KB的活性因而抑制神經膠原致癌基因的基因轉錄作用。在神經膠原致癌基因過表現的卵巢細胞，厚朴酚藉由抑制神經膠原致癌基因的基因表現，弱化其下游PI3K/Akt的訊號傳遞，降低其下游的血管內皮生長因子(VEGF)、基質金屬蛋白脢-2(MMP2)和細胞週期蛋白-D1(Cyclin D1)的基因表現。進一步證明，添加上皮生長因子(EGF)可消彌因厚朴酚作用所導致的MMP2酵素活性下降。體外細胞移動實驗證明厚朴酚可顯著的減低神經膠原致癌基因過表現卵巢癌細胞的移動能力。此外，厚朴酚可透過活化凋亡蛋白脢-3(caspase 3)和切斷聚(ADP-核糖)聚合酶(PARP)而使得神經膠原致癌基因過表現卵巢癌細胞內生性神經膠原致癌基因的基因表現，並透過弱化PI3K/Akt/mTOR訊號路徑，降低癌細胞轉型及轉移的能力。此研究提出一個厚朴酚抗癌作用的新機制。 |
| 關聯: | Cancer Letters 311(1), pp.11-19 |
| DOI: | 10.1016/j.canlet.2011.06.007 |
| 顯示於類別: | [化學學系暨研究所] 期刊論文
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