Sulforaphane在人類乳癌細胞調控AKT/mTOR/S6K路徑之探討

Sulforaphane regulates AKT/mTOR/S6K pathway in human breast cancer cells

連喬瑩(Chiao-Ying Lien)

指導教授 ： 吳志中

高雄醫學大學/藥學院/天然藥物研究所碩士班/碩士(2014年)

摘要

乳癌是全球在女性腫瘤疾病中發生最為普遍且具有第二高致死率的癌症。Tamoxifen (TM) 是乳癌的賀爾蒙療法中主要之藥物，但在目前臨床情況，已將近一半的乳癌患者無法受益於TM的治療效果，因此TM的抗藥性問題在乳癌的治療措施中將是個重要的議題。Sulforaphane (SFN) 是一個自十字花科植物分離出的化合物，已有相當多研究指出其具有抗癌的潛力和使癌細胞對化學治療敏感化。在本篇研究中，我們測試SFN對雌激素受體陽性乳癌細胞株MCF-7以及三陰性乳癌MDA-MB-468之細胞毒性，結果顯示SFN能夠濃度相關地抑制MDA-MB-468和MCF-7的細胞存活率。在機轉研究上，SFN在兩株乳癌細胞上皆能影響PDK1、AKT、mTOR、S6K和S6的磷酸化。另外，本篇實驗也發現以低濃度的SFN與TM合併使用於兩株細胞皆可以增加TM的細胞毒性，並且可以更顯著的抑制AKT、mTOR、S6K和S6的磷酸化。綜合研究結果顯示，SFN可以由抑制乳癌細胞的AKT/mTOR/S6K路徑導致細胞凋亡，而將SFN合併TM也可因抑制AKT/mTOR/S6K路徑而增加後者的抗癌活性。

關鍵字

乳癌 ； sulforaphane ； AKT ； mTOR ； tamoxifen

並列摘要

Breast cancer is the most common cancer and the second leading cause of cancer-related deaths among women worldwide. Tamoxifen (TM) has been a mainstay of endocrine therapy for both early and advanced breast cancer patients for approximately four decades. In clinical applications, there are nearly half of breast cancer patients are insensitive to TM. Therefore, the development of resistance to TM is an important issue in the treatment of breast cancer. Sulforaphane (SFN) is a compound derived from cruciferous plants and many studies have been demonstrated that SFN possesses anticancer potential and sensitizes cancer cells to chemotherapies. In this study, SFN was examined for its cytotoxic effect against an estrogen receptor positive breast cell line MCF-7 and a triple-negative (estrogen receptor, progesterone receptor, and HER2 negative) breast cancer (TNBC) cell line MDA-MB-468. Our results have demonstrated that SFN dose-dependently inhibited the cell viability of MDA-MB-468 and MCF-7 cells. In these two breast cancer cell lines, SFN significantly influenced the phosphorylation of PDK1, AKT, mTOR, S6K, and S6. In addition, a low concentration of SFN in combination with tamoxifen enhanced the cytotoxicity of the latter and significantly inhibited the phosphorylation of AKT, mTOR, S6K, and S6. Taken together, our results indicate that SFN can inhibit AKT/mTOR/S6K pathway and lead to cancer cell apoptosis. Furthermore, SFN can sensitize breast cancer cells to TM treatment through inhibition of AKT/mTOR/S6K pathway.

並列關鍵字

breast cancer ； sulforaphane ； AKT ； mTOR ； tamoxifen

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