植物性雌激素誘發乳癌細胞凋亡及抑制乳癌骨轉移的探討及機轉研究

The effects and related mechanisms of phytoestrogens on apoptosis induction and bone metastasis in breast cancer

謝佳蓉(Chia-Jung Hsieh)

指導教授 ： 蔡英美教授

高雄醫學大學/醫學院/醫學研究所博士班/博士(2015年)

https://doi.org/10.6832/KMU.2015.00033

摘要

乳癌是女性最常見的癌症疾病，婦女如果長期受到女性荷爾蒙，也就是雌激素的刺激，則較易得到乳癌。在探討植物性雌激素對人類乳癌細胞的影響中，第一部份我們發現牛蒡子的成分之一牛蒡子苷元(Arctigenin)對人類乳癌細胞株MDA-MB-231有顯著的抑制作用，且其抑制作用是透過粒線體的Bax、Bak和Bcl-2分子改變，使AIF與Endo G 蛋白釋出至細胞核內造成DNA裂解，導致細胞凋亡。此外我們亦發現Arctigenin是經由產生ROS/p38 MAPK 的途徑來誘發MDA-MB-231的凋亡，而其粒線體Bcl-2 的抑制是經由histone H3K9 trimethylation的epigenetic調控。
第二部分我們首先發現另一種植物性雌激素 wedelolactone (WDL)可以顯著地抑制乳癌細胞造成的蝕骨細胞新生(osteoclastogenesis)。WDL不僅對人類蝕骨細胞並且對乳癌細胞活化的蝕骨細胞有抑制作用，其機轉是透過抑制Akt和mTOR的訊息傳導途徑。此外MDA-MB-231乳癌細胞會促進成骨細胞和蝕骨細胞的相互作用來達到骨轉移，而WDL可以抑制此作用，其機轉是透過降低成骨細胞分泌M-CSF。
綜上所述，植物性雌激素尤其是牛蒡子苷元和WDL對乳癌細胞凋亡和乳癌骨轉移的抑制作用值得進一步臨床的探討。

關鍵字

植物性雌激素 ； 乳癌 ； 細胞凋亡 ； 骨轉移

並列摘要

Breast cancer is the leading cancer in women. Many studies show that long-term exposure to estrogen is a predisposing factor for breast cancer. To investigate the effect of phytoestrogens on human breast cancer cells, in part I, we find that arctigenin (ATG), a natural lignan product of Arctium lappa L., possesses anticancer effect in human breast cancer MDA-MB-231 cells. Results indicated that ATG induced MDA-MB-231 apoptosis by changing Bax/Bcl-2 ratios, resulting in AIF and Endo G nuclear translocation. Moreover, we find that ATG induces apoptosis of MDA-MB-231 cells via the ROS/p38 MAPK pathway, and epigenetic regulation of Bcl-2 by upregulation of histone H3K9 trimethylation.

In part II, We are the first to determine that wedelolactone (WDL), a natural coumarin isolated from plants, can inhibit breast cancer-mediated osteoclastogenesis. WDL inhibited the up-regulation of osteoclasts stimulated by MDA-MB-231 breast cancer cells. The activity of WDL on osteoclasts and breast cancer-mediated osteoclastogenesis was associated with the inhibition of Akt/mammalian target of the rapamycin signaling pathway (mTOR). Furthermore, WDL regulated breast cancer-enhanced interaction of osteoblasts and osteoclasts by decreasing M-CSF expression in MDA-MB-231-stimulated osteoblasts.

In summary, phytoestrogens, especially arctigenin and WDL, are worthy of further clinical study in inhibition of breast cancer and related bone metastasis.

並列關鍵字

phytoestrogens ； breast cancer ； apoptosis ； bone metastasis

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