蘇純立Su, Chun-Li李雨倢Lee, Yu-Jay2020-10-192025-08-102020-10-192020http://etds.lib.ntnu.edu.tw/cgi-bin/gs32/gsweb.cgi?o=dstdcdr&s=id=%22G060751011S%22.&%22.id.&http://rportal.lib.ntnu.edu.tw:80/handle/20.500.12235/111987硒（Se）為人體所需的必需營養素且被認為可預防癌症。乳癌在全球女性癌症發生率中位居第一位，患者血清Se濃度會隨著腫瘤之惡性轉移而顯著降低。Cisplatin為廣泛使用於惡性癌症的化療藥物，臨床上的使用經常伴隨凋亡性阻抗。本研究探討礦物質Se與Cisplatin同時給予對人類三陰性乳癌細胞MDA-MB-231之效用，並探討是否透過非凋亡性鐵依賴型細胞死亡（Ferroptosis）提升Cisplatin之細胞毒殺能力。結果發現，生存率較低的乳癌患者傾向胞內自由鐵之聚積，且預後較差的三陰性乳癌細胞MDA-MB-231誘發Ferroptosis之現象較管腔A型乳癌細胞MCF-7明顯。礦物質Se抑制MDA-MB-231細胞生長的效果較Zn及Fe佳，Se可提升胞內自由鐵，並在合併Cisplatin後具協同作用。Se透過提升Cisplatin處理之MDA-MB-231細胞胞內自由鐵之聚集及Lipid ROS的產生來驅動Ferroptosis，增強Cisplatin之細胞毒殺能力。同時，Se與Cisplatin的合併給予導致Nrf2下游蛋白HO-1及FTH1的表現上調。此外，Se 2 μM在低層次及高層次硒蛋白的mRNA及蛋白表現皆達飽和，故為「適當硒濃度」。綜上所述，適當的Se濃度可透過Ferroptosis改善Cisplatin治療之三陰性乳癌細胞MDA-MB-231的效果，顯示癌症患者礦物質Se狀態對於抗癌藥物之治療效果的重要性。Selenium (Se) is an essential nutrient and has a wide health benefit, including cancer prevention. Breast cancer is the first in the global incidence of female cancer. The Se level of breast cancer patient is significantly lowered with the tumor malignant metastasis. Cisplatin is a widely used chemotherapy drug for malignant cancer. Unfortunately, many cancers often develop resistance in response to cisplatin treatment. In the present study, human triple-negative breast cancer cell line MDA-MB-231 was used to explore whether Se is feasible to enhance the cytotoxic effect of cisplatin through ferroptosis, a non-apoptotic cell death. The results show that breast cancer patients with poor survival tend to accumulate intracellular free iron. Triple-negative breast cancer MDA-MB-231 cells were more susceptible to ferroptosis than luminal A breast cancer MCF-7 cells. Compared to Zn and Fe, the growth inhibition was significantly induced by Se in MDA-MB-231 cells. In addition, Se enhanced the cytotoxic of Cisplatin and produced a synergistic effect by elevating labile iron pool and lipid ROS accumulation to trigger ferroptosis in cisplatin-treated MDA-MB-231 cells. In parallel with the observation, up-regulation of FTH1 and HO-1 protein expressions was exhibited. Both high- and low-hierarchy selenoproteins were saturated at 2 μM of Se, suggesting that the experimental condition was at the ‘‘adequate level of Se’’. Overall, adequate level of Se improves the effect of cisplatin treatment in MDA-MB-231 cells through ferroptosis. In nutritional perspectives, maintaining mineral Se status in cancer patients is critical to receive benefits from treatment of anti-cancer drug.硒順鉑乳癌鐵依賴型細胞死亡三陰性乳癌SeleniumCisplatinBreast cancerFerroptosisTriple-negative breast cancer