近年來，許多的研究中顯示癌症的發生與細胞內的異常代謝具有相當大的關聯性。癌細胞具有大量消耗葡萄糖並進行乳酸發酵以快速產生能量的特性，癌細胞同時也會大量利用麩醯胺酸作為營養來源，來維持三羧酸循環的穩定，並作為蛋白質、核苷酸、脂質合成的前驅物。麩醯胺酸合成酶(GS)則可以將細胞內的麩胺酸與氨自行合成為麩醯胺酸。在先前研究當中，證明了由麩醯胺酸合成酶(GS)合成的內源性麩醯胺酸能夠促進蛋白質及核苷酸的合成，但其是否能參與調控脂質的合成尚不清楚。脂質合成有許多的酵素參與其中。三羧酸循環中的檸檬酸分解為乙醯輔酶A後，會透過acetyl-CoA carboxylase 1 (ACC1)將其轉化為丙二醯輔酶A，之後再進一步透過fatty acid synthase (FAS )轉化為脂肪酸，而SREBP1 (Sterol regulatory element-binding protein 1)為ACC1及FAS的轉錄調控因子，可調控其轉錄活性來促進脂質生成。另外有文獻指出，外加麩醯胺酸會增加SREBP1的轉錄調控因子specificity protein 1 (Sp1)的O-GlcNAcylation，進而上調SREBP1的表達量。因此在本研究中，我們想去探討麩醯胺酸合成酶(GS)對於癌細胞油滴形成的重要性，並探討其脂質形成的訊息傳導路徑。本研究結果顯示，在肝癌HepG2和乳癌MCF7細胞中，過表達麩醯胺酸合成酶(GS)會造成大量的油滴累積，且HepG2細胞的SREBP1、ACC1和O-GlcNAc-Sp1的蛋白質表現量皆有顯著的增加。在施予胰島素的處理下，敲落或抑制HepG2和MCF7細胞中的麩醯胺酸合成酶(GS)，會降低胰島素所引起的油滴累積，且HepG2細胞的SREBP1、ACC1和O-GlcNAc-Sp1的蛋白質表現量皆有顯著的下降。在麩醯胺酸缺乏的實驗中，我們發現麩醯胺酸缺乏會誘導癌細胞中麩醯胺酸合成酶(GS)的高表達，進一步去調控SREBP1、ACC1和O-GlcNAc-Sp1的蛋白質表現量而促進油滴的形成，相反地，敲落或抑制HepG2和MCF7細胞中的麩醯胺酸合成酶(GS)，會降低麩醯胺酸缺乏所引起的油滴累積，且HepG2細胞的SREBP1、ACC1和O-GlcNAc-Sp1的蛋白質表現量皆有顯著的下降。另外，我們也發現在麩醯胺酸缺乏的環境中，敲落麩醯胺酸合成酶(GS)會造成癌細胞的生長停滯。其中在麩醯胺酸加回的實驗結果中發現，在HepG2和MCF7細胞培養基中加回一倍及十倍的麩醯胺酸會降低由麩醯胺酸缺乏所引起的油滴累積，且HepG2細胞的SREBP1和ACC1的蛋白質表現量皆有顯著的下降。綜合上述所有結果顯示，麩醯胺酸合成酶(GS)能夠促進癌細胞中脂質的生成及油滴的累積，且能保護細胞在麩醯胺酸缺乏的環境中存活。

In recent years, many studies have shown that oncogenesis is closely related to dysregulated metabolism in cells. Cancer cells have the characteristics of consuming a large amount of glucose for lactic fermentation to quickly produce energy. Cancer cells also uptake glutamine as a nutrient source to fill up the tricarboxylic acid cycle and as a precursor for protein, nucleotide, and lipid synthesis. Glutamine synthetase (GS) can synthesize glutamate and ammonia into glutamine. In previous studies, it is proved that endogenous glutamine synthesized by GS can promote protein and nucleotides synthesis, but whether it can participate in the regulation of lipogenesis remains unclear. Many enzymes are involved in lipogenesis. The citrate in the tricarboxylic acid cycle is first decomposed into acetyl-CoA, and then acetyl-CoA is converted into malonyl-CoA through acetyl-CoA carboxylase 1 (ACC1). Malonyl-CoA is further converted into fatty acids through fatty acid synthase (FAS), and sterol regulatory element-binding protein 1 ( SREBP1) is a transcription factor of ACC1 and FAS, which can upregulate their expression to promote lipogenesis. Besides, it has been shown that adding a high concentration of glutamine in the medium increases the O-GlcNAcylation of the transcription factor specificity protein 1 (Sp1) of SREBP1, and then upregulates the expression of SREBP1. Therefore, in this study, we want to explore the role of GS in the regulation of lipid droplet accumulation and lipogenic pathways. Our results show that in HepG2 and MCF7 cells, overexpression of GS induces lipid droplet accumulation, and the expression of SREBP1, ACC1, and O-GlcNAc-Sp1 are also increased in HepG2 cells. Under insulin treatment, knockdown or inhibiting GS in HepG2 and MCF7 cells reduces the lipid droplet accumulation caused by insulin, and the protein expression of SREBP1, ACC1, and O-GlcNAc-Sp1 are decreased in HepG2 cells. Furthermore, we find that glutamine deprivation can induce the expression of GS with upregulated SREBP1, ACC1, and O-GlcNAc-Sp1 to promote lipid droplets formation in HepG2 and MCF7 cells. On the contrary, knocking down or inhibiting GS in HepG2 and MCF7 cells reduces the accumulation of lipid droplets caused by glutamine deprivation, and the protein expression of SREBP1, ACC1, and O-GlcNAc-Sp1 are decreased in HepG2 cells. Besides, we also find that under glutamine deprivation, knocking down GS can decrease cancer cell growth. Moreover, adding back glutamine to the HepG2 and MCF7 cell reduces the

accumulation of lipid droplets caused by glutamine deprivation, and the protein expression of SREBP1 and ACC1 in HepG2 cells are also decreased. All the above results show that GS can promote the production of lipid droplets and protect cancer cells to survive under glutamine deprivation.

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