Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20198
標題: 小鼠原位癌模式中丁香酚藉由增加內質網壓力抑制胃癌腫瘤生成以及腹膜轉移
Eugenol suppresses gastric tumor growth and peritoneal dissemination by increasing ER stress in an orthotopic model
作者: 賴德偉
Lai, De-Wei
關鍵字: 丁香酚(Eugenol);Eugenol;芳香烴受體(AHR);鈣蛋白酶-10;gastric cancer;calpain;peritoneal dissemination;aryl hydrocarbon receptor
出版社: 生物醫學研究所
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摘要: 
丁香酚(4-allyl-2-methoxyphenol)已經知道具有抗發炎的功用, 但是在抑制癌症以及抑制腹膜轉移的機制尚未清楚。在本研究中,我們的目的是評估在體內和體外的抗腫瘤生長和抗轉移的潛力。我們的結果發現,經由丁香酚處理原位植入MKN45胃癌細胞的小鼠不管在腫瘤的生長以及腹膜傳播和肝/肺轉移有顯著減少,並且伴隨著誘導細胞凋亡。此外,在給予丁香酚後,在胃癌細胞中發現相對增加內質網壓力的標記蛋白,GADD153,IRE1a,P-PERK,P-elf2a,Caspase7等蛋白表達。另外芳香烴受體(AHR)和COX-2是環境致癌物的活化轉錄因子與腫瘤發生和轉移因子。同時,丁香酚處理也減少了AhR/RelA相互作用和COX-2 基因的表達。如同上述,我們使用AGS SCM-1和N87胃癌細胞在體外處理皆可發現相同結果。因此進一步在細胞凋亡的部分我們發現在給予丁香酚後,胃癌細胞增加內質網壓力的標記蛋白GADD153和死亡受體5主要是經由增加(CHOP)/ DR5上游啟動子結合活性,但不是死亡受體4。此外,丁香酚處理後的胃癌細胞中AhR的降解和在內質網產生壓力有相關聯性,如同上述內質網產生壓力時相對產生特定鈣蛋白酶-10和AhR的相互作用增加,促使將AhR蛋白的降解,但不是鈣蛋白酶-1或鈣蛋白酶-2。沉默鈣蛋白酶-10可以發現相對應的抑制由丁香酚治療的生物效應。而不管在隨著時間或濃度劑量效應都可以發現丁香酚處理後AhR/RelA相互作用減少也會相對影響核易位和在腫瘤細胞中的DNA結合活性並且活化鈣蛋白酶-10將AhR降解。兩者合計,我們的研究結果表明,丁香酚抑制胃腫瘤的生長和腹膜轉移是經由激活內質網壓力和誘導細胞凋亡。

Eugenol (4-allyl-2-methoxyphenol) is known to suppress the inflammation; however, its anti-tumor growth, anti-peritoneal dissemination effects have not been studied so far in orthotopic mouse model. In the present study, we aimed to evaluate the anti-tumor growth and anti-metastatic potential of Eugenol in vivo and in vitro. Our results demonstrate that tumor growth, peritoneal dissemination and liver/lung metastasis of orthotopically implanted MKN45 cells were significantly reduced in Eugenol-treated mice along with the induction of apoptosis. Furthermore, Eugenol-treated tumors showed increased ER stress signature such as increased expression of IRE1a, GADD153, p-PERK, p-elf2a, Caspase7. The aryl hydrocarbon receptor (AhR) and COX-2 is an environmental carcinogen-activated transcription factor associated with tumorigenesis and metastasis. Simultaneously, Eugenol-treated also decreased cooperation of AhR/NF-kB/RelA and COX-2 expression. Similar observations were made when SCM-1, AGS and N87 cells were treated in vitro. Eugeno-induced upregulation of death receptor 5 by increase GADD153(CHOP)/DR5 binding activity but not death receptor 4. Moreover, AhR was down-regulated and cleavaged in the ER fraction of Eugenol-treated cells, as indicated by increased interaction of specific Calpain-10, but not Calpain-1 or Calpain-2. Silence Calpain-10 was abrogated by Eugenol treatment biological effects. In addition, Eugenol inhibited AhR/NF-kB/RelA interaction, nuclear translocation and DNA binding activity in cancer cells in time course and dose-dependent manner by Calpain-10 activation. Taken together, our results suggest that Eugenol suppresses both gastric tumor growth and peritoneal dissemination by inducing apoptosis and activating ER stress.
URI: http://hdl.handle.net/11455/20198
其他識別: U0005-0107201314491000
Appears in Collections:生物醫學研究所

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