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    题名: 小蘖鹼可能藉由 p185HER2/neu 蛋白質降解進而抑制神經膠原致癌基因過表現引起的細胞增生與轉移
    其它题名: Berberine may inhibit cell proliferation and metastasis via degradation of p185HER2/neu in HER2/neu-overexpressing cancer cells
    作者: 林映妤;Lin, Ying-yu
    贡献者: 淡江大學化學學系碩士班
    莊子超;Chuang, Tzu-chao
    关键词: 小蘖鹼;神經膠原致癌基因;轉移;Berberine;HER2/neu;Metastasis
    日期: 2008
    上传时间: 2010-01-11 02:49:50 (UTC+8)
    摘要: 小蘖鹼為一種異喹啉生物鹼,存在於小蘖科植物的根、莖或樹皮中,具有抗心律不整及抗腫瘤的功效。為了找出小蘖鹼在 HER2/neu 過表現細胞中的化學預防分子作用機制,我們分析數個不同 p185HER2/neu 蛋白質表現量的細胞株,結果發現相較於正常 HER2/neu 表現量的細胞株,小蘖鹼會針對 HER2/neu 過表現的細胞株有較高抑制細胞存活率的效果。此外小蘖鹼在 HER2/neu 過表現的細胞株會有依劑量及依時間抑制 p185HER2/neu 蛋白質表現量的情形。進一步觀察發現小蘖鹼會抑制 p185HER2/neu 的活性及其下游 Akt 與 ERK 的活性。此外我們發現小蘖鹼會抑制 p185HER2/neu 過表現的卵巢癌細胞 (SKOV3) 的轉移能力。另外也證明了 EGF 會回覆藉由小蘖鹼所抑制的 MMP2 的活性,而 PI3K 的抑制劑會抑制由 EGF 所回覆的 MMP2 活性。綜合所有的實驗結果可說明,小蘖鹼會促進 p185HER2/neu 蛋白質降解而造成 HER2/neu 過表現細胞的損壞,並藉由抑制PI3K/Akt 訊號路徑進而減弱了由 p185HER2/neu 所調控的轉移情形。
    Berberine, an isoquinoline alkaloid, present in the roots, rhizome and stem bark of Berberis species, has been shown to possess potent anti-arrhythmic and anti-turmor properties. To explore the molecular mechanism of the chemopreventive effects of berberine in the HER2/neu-overexpressing cancer cells, we examined several human cancer cell lines having different levels p185HER2/neu expression and found that berberine exhibited much more growth-inhibitory activity in the HER2/neu-overexpressing cancer cells than those cells expressing basal levels of p185HER2/neu. Depletion of p185HER2/neu was also observed in HER2/neu-overexpressing cancer cells in a dose- and time-dependant manner. We also demonstrate that berberine can downregulate the activated form of p185HER2/neu as well as Akt and ERK, downstream substrates of p185HER2/neu. Furthermore, we found that berberine is potent in suppressing transformation phenotype of SKOV3 cells (HER2/neu-overexpressing ovarian cancer cell) including metastasis-associated properties. We also elucidate that EGF specifically restores the activation of MMP2 after its activity was reduced by berberine; the restoration of MMP2 activity was also inhibited by PI3K inhibitor. These finding suggest that berberine can cause HER2/neu-overexoressing cancer cell damage by inducing degradation of p185HER2/neu, and then inhibiting the PI3K/Akt-signaling pathway to attenuate the p185HER2/neu mediated metastasis.
    显示于类别:[化學學系暨研究所] 學位論文

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