CPO 對子宮內膜癌訊息傳遞路徑之影響

由以上細胞測試發現，在不影響細胞存活率的低劑量處理下 CPO 對於 RL95-2 與 HEC-1A 子宮內膜癌細胞的移行及侵襲特性確實有抑制的效果。

於是將使用細胞溶解液來進行西方墨點法試驗，以進一步了解 CPO 影響細

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58 2010; Fiaschetti et al., 2011)、醌類 (Sun et al., 2010; Verrax et al., 2011)、倍半 萜內酯 (Ghantous et al., 2010; Merfort et al., 2011) 以及它們的衍生物 (Tamura et al., 2002; Vaclavikova et al., 2006) 通常具有較高的生物活性。

最近研究已證實許多天然植物萃取物中的活性成分具有抑制癌細胞生長 及轉移的功效，如雷公藤 (Tripterygium wilfordii) 的 triptolide 已被證明能夠 抑制細胞增殖，誘導腫瘤細胞凋亡並具有抑制小鼠移植瘤乳腺癌、胃癌、膀 胱癌和胰腺癌的腫瘤生長和轉移(Chang et al., 2001; Kiviharju et al., 2002;

Yang et al., 2003; Phillips et al., 2007)；蕃茄 (Lycopersicon esculentum) 中的 α-tomatine 可藉由抑制 PI3K/Akt 與 ERK 訊號傳遞路徑，減少基質金屬蛋白酵 素 MMP-2 與 MMP-9 的活性，進而阻止肺癌細胞 A549 的移行與侵襲 (Shih et al., 2009)；薑黃 (Curcuma longa) 中的活性成分 curcumin 已被證實可抑制 細胞增殖誘導細胞凋亡與抑制癌細胞的侵襲、血管增生和轉移(Menon et al., 1999)；雲南重樓 (Rhizoma Paridis) 中的 saponins 可以誘導癌細胞凋亡，促進 基質金屬蛋酵素抑制因子-2 (Tissue inhibitors of metalloproteinase-2)的表現，

同時減少 MMP-2 與 MMP-9 的活性，進而抑制癌細胞的轉移(Man et al.,

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胞侵襲中非常重要的初始步驟，藉由此方式癌細胞及可脫離原來的病灶轉移 到 新 的 部 位 ， 甚 至 是 進 入 血 液 經 淋 巴 循 環 進 行 轉 移 至 遠 處 的 重 要 器 官 (Liabakk et al., 1996; Johnsen et al., 1998)。

MAPK 路徑參予了細胞增生、凋亡、調節細胞激素的表現及 MMPs 的 產生及活化等過程，而 MAPK 家族中包含了 extracellular signal-regulated kinase (ERK)、c-Jun N-terminal kinase (JNK)及 p38 kinase，而當 MAPK 路徑 被磷酸化會導致 MMPs 大量產生之後，會使得細胞具有較強的能力來分解細 胞外基質，產生局部侵襲及移行(Wu, 2006; Lee et al., 2007; Lee et al., 2008)。

此外，當 phosphatidylinositol-3-kinase (PI3K)/Akt pathway 被磷酸化時會刺激 MMP-9 的產生並使癌細胞產生侵襲及轉移的行為 (Chen et al., 2009)。Lu et al.

(2013)的研究中指出，Akt 及 MAPK 路徑參與了調節 uPA 及 MMPs 的過程，

抑制 p-Akt 便可降低 MMP-2 及 uPA 的表現，進而抑制癌細胞的侵襲作用。

因此，本研究針對 MAPK 路徑、Akt、uPA、MMP-2、MMP-9 等與轉移、侵 襲相關之蛋白質做進一步的機制探討。 Wound healing assay、Cell migration assay 及 cell invasion assay 分析之結果顯 示，CPO 具有抑制子宮內膜癌細胞的移行及侵襲的效果，並與 CPO 劑量呈 現依存性。藉由 Western blot 進行機制探討，結果顯示 CPO 可藉由抑制 p-Akt 及 MAPK 路徑的蛋白質表現進而使 MMP-2、MMP-9 與 uPA 等相關轉移 蛋白質表現下降而達到抗轉移的效果。

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第五章

總 結

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本研究首次證實台灣種希仙草對於子宮內膜癌 RL95-2 細胞具有抗癌活 性，並且釐清了可能的抗癌作用機轉。研究結果證實，SOE 對於子宮內膜癌 之生長具有顯著抑制效果，且呈現劑量與時間性關係；並進一步發現經 SOE 作用後會誘導 RL95-2 細胞皺縮、空泡化、細胞膜脹破，且造成細胞懸浮，

呈現細胞走向計畫性凋亡之特徵。藉由流式細胞儀分析結果顯示 SOE 可使 細胞生長停滯於 G2/M 生長期，並誘導細胞走向凋亡。此外，SOE 可向上調 控 Bad、Bax 及 Bak 等凋亡蛋白，並向下調控 Bcl-2 及 Bcl-xL 等抗凋亡蛋 白，進而活化下游 caspase 活性，最終達成細胞凋亡。圖 5-1 為綜合這些結 果所彙整之基因訊息傳遞路徑。藉由 GC-MS 化學組成分析及細胞毒性測試 結果顯示，CP 與 CPO 兩個化合物應為 SOE 的主要抗癌活性成份。

圖 5-1、SOE 對於子宮內膜癌細胞凋亡過程中所引發之基因訊息傳遞路徑及 其調節機制。

此外，進一步針對 SOE 及其可能有效成分 CPO 對癌細胞遷移、移行及 侵襲作用進行探討，以瞭解 SOE 及 CPO 抗 RL95-2、HEC-1A 子宮內膜癌細 胞轉移之功效。實驗結果發現，經 SOE 及 CPO 作用後可抑制受 TGFβ1 所誘

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導之子宮內膜癌 EMT 現象，藉由 Wound healing assay、Cell migration assay 及 Cell invasion assay 分析結果顯示，SOE 及 CPO 可抑制經 TGFβ1 所誘導之 子宮內膜癌 EMT 現象，並可抑制 uPA 酵素活性，以阻斷 pro-MMPs 轉換成 活化態的 MMPs，造成 MMP-2 與 MMP-9 活性降低，並向下調控 p-AKT 及 MAPK pathway 等轉移蛋白，進而阻止癌細胞的遷移、移行及侵襲作用和癌 細胞降解細胞外基質的能力，最終達到抗轉移之效果。圖 5-2 及 5-3 為綜合 這些結果所彙整之基因訊息傳遞路徑。因此，本研究證實希仙草萃取物確實 可抑制 RL95-2、HEC-1A 子宮內膜癌細胞生長、遷移、移行及侵襲作用，而 其有效成分 CPO 具有與 SOE 相似的抑制癌細胞生長與轉移效果和訊息傳遞 路徑，因此證實 CPO 為 SOE 的主要抗癌活性成份。

圖 5- 2、SOE 對於子宮內膜癌細胞轉移過程中所引發之訊息傳遞路徑及其調 節機制。

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圖 5- 3、CPO 對於子宮內膜癌細胞轉移過程中所引發之訊息傳遞路徑及其調 節機制。

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